1
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Abid D, Murphy K, Murphy Z, Rahman N, Getman M, Steiner L. The Condensin II complex regulates essential gene expression programs during erythropoiesis. Development 2025; 152:dev204485. [PMID: 40260585 DOI: 10.1242/dev.204485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 04/04/2025] [Indexed: 04/23/2025]
Abstract
Erythropoiesis is characterized by dramatic changes in gene expression in the context of a cell that is rapidly proliferating while simultaneously condensing its nucleus in anticipation of enucleation. The mechanisms that maintain high level expression of erythroid genes and promote nuclear condensation remain poorly understood. Condensin II is a ring-like complex that promotes mitotic chromatin condensation and has roles in regulating interphase chromatin architecture and gene expression. We interrogated the role of Condensin II in erythropoiesis using an erythroid-specific deletion of the Condensin II subunit, Ncaph2. Ncaph2 loss resulted in severe anemia by embryonic day 12.5 with embryonic lethality. Ncaph2 mutant erythroid cells had dysregulated maturation and disrupted cell cycle progression, but surprisingly NCAPH2 was dispensable for nuclear condensation. Genomic studies revealed that NCAPH2 occupied the promoter of key erythroid and cell cycle genes that were downregulated following Ncaph2 loss. Together, our results demonstrate an essential role for NCAPH2 in the gene expression programs that regulate cell cycle progression and erythroid differentiation, and identify a role for the Condensin II complex in the regulation of a lineage-specific differentiation program.
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Affiliation(s)
- Deanna Abid
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Kristin Murphy
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Zachary Murphy
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Biology, St John Fisher University, Rochester, NY 14618, USA
| | - Nabil Rahman
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Michael Getman
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Laurie Steiner
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Center for RNA Biology, University of Rochester, Department of Pediatrics, Rochester, NY 14642, USA
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2
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Mihalas AB, Arora S, O'Connor SA, Feldman HM, Cucinotta CE, Mitchell K, Bassett J, Kim D, Jin K, Hoellerbauer P, Delegard J, Ling M, Jenkins W, Kufeld M, Corrin P, Carter L, Tsukiyama T, Aronow B, Plaisier CL, Patel AP, Paddison PJ. KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma. Nat Commun 2025; 16:4327. [PMID: 40346033 PMCID: PMC12064679 DOI: 10.1038/s41467-025-59503-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 04/22/2025] [Indexed: 05/11/2025] Open
Abstract
Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.
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Affiliation(s)
- Anca B Mihalas
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Sonali Arora
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Samantha A O'Connor
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA
| | - Heather M Feldman
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Christine E Cucinotta
- College of Arts and Sciences, Department of Molecular Genetics, Ohio State University, Columbus, OH, 43210, USA
- Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Kelly Mitchell
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - John Bassett
- Department of Medicine, Karolinska Institute, Huddinge, Sweden
| | - Dayoung Kim
- Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Kang Jin
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Pia Hoellerbauer
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Jennifer Delegard
- Department of Neurosurgery, University of Washington, Seattle, WA, 98195, USA
| | - Melissa Ling
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98195, USA
| | - Wesley Jenkins
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98195, USA
| | - Megan Kufeld
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Philip Corrin
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Lucas Carter
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Toshio Tsukiyama
- Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Bruce Aronow
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Christopher L Plaisier
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA
| | - Anoop P Patel
- Department of Neurosurgery, Duke University, Durham, NC, 27710, USA.
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, 27710, USA.
- Center for Advanced Genomic Technologies, Duke University, Durham, NC, 27710, USA.
| | - Patrick J Paddison
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98195, USA.
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3
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Zemaitis KJ, Paša-Tolić L. Challenges in Spatial Metabolomics and Proteomics for Functional Tissue Unit and Single-Cell Resolution. Semin Nephrol 2025:151583. [PMID: 40263091 DOI: 10.1016/j.semnephrol.2025.151583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
In the last decade, advanced developments of mass spectrometry-based assays have made spatial measurements of hundreds of metabolites and thousands of proteins not only possible, but routine. The information obtained from such mass spectrometry imaging experiments traces metabolic events and helps decipher feedback loops across anatomical regions, connecting genetic and metabolic networks that define phenotypes. Herein we overview developments in the field over the past decade, highlighting several case studies demonstrating direct measurement of metabolites, proteins, and proteoforms from thinly sliced tissues at the level of functional tissue units, approaching single-cell levels. Much of this work is feasible due to multidisciplinary team science, and we offer brief perspectives on paths forward and the challenges that persist with adoption and application of these spatial omics techniques at the single-cell level on mammalian kidneys. Data analysis and reanalysis still pose issues that plague spatial omics, but many mass spectrometry imaging platforms are commercially available. With greater harmonization across platforms and rigorous quality control, greater adoption of these platforms will undoubtedly provide major insights in complex diseases. Semin Nephrol 36:x-xx © 20xx Elsevier Inc. All rights reserved.
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Affiliation(s)
- Kevin J Zemaitis
- Analytical Chemistry Staff Scientist, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Ljiliana Paša-Tolić
- Chemistry Laboratory Fellow and Lead Scientist for Visual Proteomics, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
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4
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Zhang T, Guerra LF, Berlina Y, Wilson JR, Fierz B, Müller MM. Semisynthesis of Isomerized Histone H4 Reveals Robustness and Vulnerability of Chromatin toward Molecular Aging. J Am Chem Soc 2025; 147:4952-4961. [PMID: 39894946 PMCID: PMC11826994 DOI: 10.1021/jacs.4c14136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 02/04/2025]
Abstract
Proteins are subject to aging in the form of spontaneous, nonenzymatic post-translational modifications (PTMs). One such PTM is the formation of the β-linked isomer l-isoaspartic acid (isoAsp) from aspartic acid (Asp) or asparagine residues, which tends to occur in long-lived proteins. Histones can exhibit half-lives on the order of 100 days, and unsurprisingly, isoAsp formation has been observed in nearly every histone family. Delineating the molecular consequences of isoAsp formation in histones is challenging due to the multitude of processes that occur on such time scales. To isolate the effects of a specific isoAsp modification thus necessitates precise in vitro characterization with well-defined substrates. Here, we adapt a protein semisynthesis approach to generate full-length variants of histone H4 in which the canonical Asp at position 24 is replaced by its isoAsp isomer (H4isoD24). This variant was incorporated into chromatin templates, and the resulting constructs were used to interrogate key parameters of chromatin integrity and maintenance in vitro: compaction, nucleosome remodeling, and methylation of H4 lysine 20 (H4K20). Remarkably, despite its disruptive changes to the backbone's spacing and direction, isoD24 did not dramatically disrupt Mg2+-mediated chromatin self-association or nucleosome repositioning by the remodeler Chd1. In contrast, H4isoD24 significantly inhibited both Set8- and Suv4-20h1-catalyzed methylation at H4K20. These results suggest that H4isoD24 gives rise to a complex reorganization of the chromatin functional landscape, in which macroscopic processes show robustness and local mechanisms exhibit vulnerability to the presence of this mark.
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Affiliation(s)
- Tianze Zhang
- Department
of Chemistry, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
| | - Luis F. Guerra
- Department
of Chemistry, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
| | - Yana Berlina
- École
Polytechnique Fédérale de Lausanne (EPFL), ISIC, Lausanne CH-1015, Switzerland
| | - Jon R. Wilson
- The
Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
| | - Beat Fierz
- École
Polytechnique Fédérale de Lausanne (EPFL), ISIC, Lausanne CH-1015, Switzerland
| | - Manuel M. Müller
- Department
of Chemistry, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
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5
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Choi DK. Epigenetic regulation of angiogenesis and its therapeutics. Genomics Inform 2025; 23:4. [PMID: 39934895 DOI: 10.1186/s44342-025-00038-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/19/2025] [Indexed: 02/13/2025] Open
Abstract
Angiogenesis, the formation of new blood vessels from preexisting ones, is essential for normal development, wound healing, and tissue repair. However, dysregulated angiogenesis is implicated in various pathological conditions, including cancer, diabetic retinopathy, and atherosclerosis. Epigenetic modifications, including DNA methylation, histone modification, and noncoding RNAs (e.g., miRNAs), play a crucial role in regulating angiogenic gene expression without altering the underlying DNA sequence. These modifications tightly regulate the balance between pro-angiogenic and anti-angiogenic factors, thereby influencing endothelial cell proliferation, migration, and tube formation. In recent years, epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., azacitidine, decitabine), histone deacetylase inhibitors (e.g., vorinostat, romidepsin), and BET inhibitors (e.g., JQ1), have emerged as promising therapeutic strategies for targeting abnormal angiogenesis. These agents modulate gene expression patterns, reactivating silenced tumor suppressor genes while downregulating pro-angiogenic signaling pathways. Additionally, miRNA modulators, such as MRG-110 and MRG-201, provide precise regulation of angiogenesis-related pathways, demonstrating significant therapeutic potential in preclinical models. This review underscores the intricate interplay between epigenetic regulation and angiogenesis, highlighting key mechanisms and therapeutic applications. Advancing our understanding of these processes will enable the development of more effective and targeted epigenetic therapies for angiogenesis-related diseases, paving the way for innovative clinical interventions.
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Affiliation(s)
- Dong Kyu Choi
- BK21 FOUR KNU Creative BioResearch Group, School of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea.
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6
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Zhang J, Donahue G, Gilbert MB, Lapidot T, Nicetto D, Zaret KS. Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programmes and repeats in pluripotent cells. Nat Cell Biol 2024; 26:2115-2128. [PMID: 39482359 DOI: 10.1038/s41556-024-01547-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 09/27/2024] [Indexed: 11/03/2024]
Abstract
H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1 hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12-24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A 'binary switch' governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12 h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3 heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency.
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Affiliation(s)
- Jingchao Zhang
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Greg Donahue
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael B Gilbert
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USA
| | - Tomer Lapidot
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Dario Nicetto
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
- Department Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Kenneth S Zaret
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
- Department Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
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7
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Arroyo M, Casas-Delucchi C, Pabba M, Prorok P, Pradhan S, Rausch C, Lehmkuhl A, Maiser A, Buschbeck M, Pasque V, Bernstein E, Luck K, Cardoso M. Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome. Nucleic Acids Res 2024; 52:11659-11688. [PMID: 39189450 PMCID: PMC11514477 DOI: 10.1093/nar/gkae734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 08/07/2024] [Accepted: 08/14/2024] [Indexed: 08/28/2024] Open
Abstract
MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability. Moreover, macroH2A1, but not macroH2A2, regulates the number of nano replication foci in the Xi, and macroH2A1 downregulation increases DNA loop sizes corresponding to replicons. This relates to macroH2A1 regulating replicative helicase loading during G1 by interacting with it. We mapped this interaction to a phenylalanine in macroH2A1 that is not conserved in macroH2A2 and the C-terminus of Mcm3 helicase subunit. We propose that macroH2A1 enhances the licensing of pre-replication complexes via DNA helicase interaction and loading onto the Xi.
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Affiliation(s)
- Maria Arroyo
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Corella S Casas-Delucchi
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Maruthi K Pabba
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Paulina Prorok
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Sunil K Pradhan
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Cathia Rausch
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Anne Lehmkuhl
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
| | - Andreas Maiser
- Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, LMU Munich, Munich 81377, Germany
| | - Marcus Buschbeck
- Program of Myeloid Neoplasms, Program of Applied Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, Camí de les Escoles, 08916 Badalona, Barcelona, Spain
| | - Vincent Pasque
- Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single-Cell Omics (LISCO), KU Leuven-University of Leuven, 3000 Leuven, Belgium
| | - Emily Bernstein
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, NY, NY 10029, USA
| | - Katja Luck
- Institute of Molecular Biology (IMB) gGmbH, 55128 Mainz, Germany
| | - M Cristina Cardoso
- Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
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8
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Du Y, He Z, Jin S, Jin G, Wang K, Yang F, Zhang J. Targeting histone methylation and demethylation for non-alcoholic fatty liver disease. Bioorg Chem 2024; 151:107698. [PMID: 39126869 DOI: 10.1016/j.bioorg.2024.107698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, facing increasing challenges in terms of prevention and treatment. The methylation of lysine and arginine residues on histone proteins is dynamically controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs), regulating chromatin structure and gene transcription. Mutations, genetic translocations, and altered gene expression involving HMTs and HDMs are frequently observed in NAFLD. HMTs and HDMs are receiving increasing attention in regulating NALFD. Targeting specific HMTs and HDMs for drug development is becoming a new strategy for treating NAFLD. This review provides a comprehensive summary of the regulatory mechanism of histone methylation/demethylation in NAFLD. Additionally, we discuss the potential applications of HMTs and HDMs inhibitors in preventing NAFLD, which may provide a scientific basis for the treatment of NAFLD.
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Affiliation(s)
- Yuanbing Du
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Zhangxu He
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Sasa Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Gang Jin
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Kaiyue Wang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China
| | - Feifei Yang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
| | - Jingyu Zhang
- Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
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9
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Park S, Cho JH, Kim JH, Kim JA. Histone lysine methylation modifiers controlled by protein stability. Exp Mol Med 2024; 56:2127-2144. [PMID: 39394462 PMCID: PMC11541785 DOI: 10.1038/s12276-024-01329-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 10/13/2024] Open
Abstract
Histone lysine methylation is pivotal in shaping the epigenetic landscape and is linked to cell physiology. Coordination of the activities of multiple histone lysine methylation modifiers, namely, methyltransferases and demethylases, modulates chromatin structure and dynamically alters the epigenetic landscape, orchestrating almost all DNA-templated processes, such as transcription, DNA replication, and DNA repair. The stability of modifier proteins, which is regulated by protein degradation, is crucial for their activity. Here, we review the current knowledge of modifier-protein degradation via specific pathways and its subsequent impact on cell physiology through epigenetic changes. By summarizing the functional links between the aberrant stability of modifier proteins and human diseases and highlighting efforts to target protein stability for therapeutic purposes, we aim to promote interest in defining novel pathways that regulate the degradation of modifiers and ultimately increase the potential for the development of novel therapeutic strategies.
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Affiliation(s)
- Sungryul Park
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Jin Hwa Cho
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Jeong-Hoon Kim
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
- Department of Bioscience, University of Science and Technology, Daejeon, South Korea.
| | - Jung-Ae Kim
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
- Department of Bioscience, University of Science and Technology, Daejeon, South Korea.
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
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10
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Zhang J, Donahue G, Gilbert MB, Lapidot T, Nicetto D, Zaret KS. Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programs and repeats in pluripotent cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.16.613328. [PMID: 39345615 PMCID: PMC11429881 DOI: 10.1101/2024.09.16.613328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
H3K9me3-heterochromatin, established by lysine methyltransferases (KMTs) and compacted by HP1 isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3-heterochromatin stability is presently limited to individual domains and DNA repeats. We engineered Suv39h2 KO mouse embryonic stem cells to degrade remaining two H3K9me3-KMTs within one hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12-24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A "binary switch" governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMTs' depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening, and exit from pluripotency within 12 hr. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3-heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency.
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Affiliation(s)
- Jingchao Zhang
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Dept. Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Greg Donahue
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Dept. Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Michael B. Gilbert
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Tomer Lapidot
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Dario Nicetto
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Dept. Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Kenneth S. Zaret
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Dept. Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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11
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Díaz-Pérez L, Salusso A, Patolsky R, Mayol G, Quassollo G, Feliziani C, Touz MC, Rópolo AS. Lysine methyltransferase 2 plays a key role in the encystation process in the parasite Giardia lamblia. Acta Trop 2024; 257:107295. [PMID: 38906362 DOI: 10.1016/j.actatropica.2024.107295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/23/2024]
Abstract
Histone post-translational modifications are extensively studied for their role in regulating gene transcription and cellular environmental adaptation. Research into these modifications has recently begun in the protozoan parasite Giardia lamblia, focusing on histone-modifying enzymes and specific post-translational changes. In the transformation from the trophozoite to the cyst form in the life cycle of this parasite, significant morphological and genetic alterations occur, culminating in the synthesis of cyst wall proteins responsible for forming the protective cyst wall. It has been previously demonstrated that histone deacetylation is required during encystation and that the enzyme lysine methyltransferase 1 is involved in the upregulation of encystation. Our study aims to extend the analysis to lysine methyltransferase 2 (GlKMT2) function. For this, two constructs were generated: one that downregulate the expression of GLKMT2 via antisense (glkmt2-as transgenic cells) and the other overexpressing GlKMT2 (glkmt2-ha transgenic cells). We found that the glktm2-as transgenic cells showed an arrest in progress at the late encystation stage. Consequently, the number of cysts produced was lower than that of the control cells. On the other hand, we found that the overexpression of GlKMT2 acts as a negative mutant of the enzyme. In this way, these glktm2-ha transgenic cells showed the same behavior during growth and encystation as glkmt2-as transgenic cells. This interplay between different enzymes acting during encystation reveals the complex process behind the differentiation of the parasite. Understanding how these enzymes play their role during the encystation of the parasite would allow the design of inhibitors to control the parasite.
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Affiliation(s)
- Luciano Díaz-Pérez
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Agostina Salusso
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Rocío Patolsky
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gonzalo Mayol
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) - Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Ciudad Autónoma de Buenos Aires, Argentina
| | - Gonzalo Quassollo
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Constanza Feliziani
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - María Carolina Touz
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Andrea S Rópolo
- Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina.
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12
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Luo Y, Lu J, Lei Z, Zhu H, Rao D, Wang T, Fu C, Zhang Z, Xia L, Huang W. Lysine methylation modifications in tumor immunomodulation and immunotherapy: regulatory mechanisms and perspectives. Biomark Res 2024; 12:74. [PMID: 39080807 PMCID: PMC11289998 DOI: 10.1186/s40364-024-00621-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024] Open
Abstract
Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.
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Affiliation(s)
- Yiming Luo
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Junli Lu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhen Lei
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - He Zhu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Dean Rao
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Tiantian Wang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Chenan Fu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhiwei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Wenjie Huang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China.
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13
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Srivastava A, Ahmad R, Yadav K, Siddiqui S, Trivedi A, Misra A, Mehrotra S, Ahmad B, Ali Khan M. An update on existing therapeutic options and status of novel anti-metastatic agents in breast cancer: Elucidating the molecular mechanisms underlying the pleiotropic action of Withania somnifera (Indian ginseng) in breast cancer attenuation. Int Immunopharmacol 2024; 136:112232. [PMID: 38815352 DOI: 10.1016/j.intimp.2024.112232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/14/2024] [Accepted: 05/07/2024] [Indexed: 06/01/2024]
Abstract
Major significant advancements in pharmacology and drug technology have been made to heighten the impact of cancer therapies, improving the life expectancy of subjects diagnosed with malignancy. Statistically, 99% of breast cancers occur in women while 0.5-1% occur in men, the female gender being the strongest breast cancer risk factor. Despite several breakthroughs, breast cancer continues to have a worldwide impact and is one of the leading causes of mortality. Additionally, resistance to therapy is a crucial factor enabling cancer cell persistence and resurgence. As a result, the search and discovery of novel modulatory agents and effective therapies capable of controlling tumor progression and cancer cell proliferation is critical. Withania somnifera (L.) Dunal (WS), commonly known as Indian ginseng, has long been used traditionally for the treatment of several ailments in the Indian context. Recently, WS and its phytoconstituents have shown promising anti-breast cancer properties and, as such, can be employed as prophylactic as well as therapeutic adjuncts to the main line of breast cancer treatment. The present review is an attempt to explore and provide experimental evidences in support of the prophylactic and therapeutic potential of WS in breast cancer, along with a deeper insight into the multiple molecular mechanisms and novel targets through which it acts against breast and other hormonally-induced cancers viz. ovarian, uterine and cervical. This exploration might prove crucial in providing better understanding of breast cancer progression and metastasis and its use as an adjunct in improving disease prognosis and therapeutic outcome.
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Affiliation(s)
- Aditi Srivastava
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Rumana Ahmad
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Kusum Yadav
- Dept. of Biochemistry, University of Lucknow, Lucknow 226007, UP., India.
| | - Sahabjada Siddiqui
- Dept. of Biotechnology, Era's Lucknow Medical College & Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Anchal Trivedi
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Aparna Misra
- Dept. of Biochemistry, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Sudhir Mehrotra
- Dept. of Biochemistry, University of Lucknow, Lucknow 226007, UP., India.
| | - Bilal Ahmad
- Research Cell, Era University, Sarfarazganj, Hardoi Road, Lucknow 226003, UP., India.
| | - Mohsin Ali Khan
- Dept. of Research & Development, Era University, Lucknow 226003, UP., India.
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14
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Galanopoulou O, Tachmatzidi EC, Deligianni E, Botskaris D, Nikolaou KC, Gargani S, Dalezios Y, Chalepakis G, Talianidis I. Endonucleosis mediates internalization of cytoplasm into the nucleus. Nat Commun 2024; 15:5843. [PMID: 38992049 PMCID: PMC11239883 DOI: 10.1038/s41467-024-50259-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 07/03/2024] [Indexed: 07/13/2024] Open
Abstract
Setd8 regulates transcription elongation, mitotic DNA condensation, DNA damage response and replication licensing. Here we show that, in mitogen-stimulated liver-specific Setd8-KO mice, most of the hepatocytes are eliminated by necrosis but a significant number of them survive via entering a stage exhibiting several senescence-related features. Setd8-deficient hepatocytes had enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles surrounded by nuclear lamina. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process "endonucleosis". Intranuclear vesicles are absent in hepatocytes of Setd8/Atg5 knockout mice, suggesting that the process requires the function of the canonical autophagy machinery. Endonucleosis and hyperploidization are temporary, early events in the surviving Setd8-deficient cells. Larger vesicles break down into microvesicles over time and are eventually eliminated. The results reveal sequential events in cells with extensive DNA damage, which function as part of survival mechanisms to prevent necrotic death.
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Affiliation(s)
- Ourania Galanopoulou
- Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece
- Dept. of Biology University of Crete, Heraklion, Crete, Greece
| | - Evangelia C Tachmatzidi
- Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece
- Dept. of Biology University of Crete, Heraklion, Crete, Greece
| | - Elena Deligianni
- Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece
| | - Dimitris Botskaris
- Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece
- Dept. of Biology University of Crete, Heraklion, Crete, Greece
| | | | - Sofia Gargani
- Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
| | - Yannis Dalezios
- School of Medicine University of Crete, Heraklion, Crete, Greece
| | | | - Iannis Talianidis
- Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece.
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15
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Sato Y, Takenoshita M, Ueoka M, Ueda J, Yamagata K, Kimura H. Visualizing histone H4K20me1 in knock-in mice expressing the mCherry-tagged modification-specific intracellular antibody. Histochem Cell Biol 2024; 162:41-52. [PMID: 38762823 PMCID: PMC11227479 DOI: 10.1007/s00418-024-02296-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2024] [Indexed: 05/20/2024]
Abstract
During development and differentiation, histone modifications dynamically change locally and globally, associated with transcriptional regulation, DNA replication and repair, and chromosome condensation. The level of histone H4 Lys20 monomethylation (H4K20me1) increases during the G2 to M phases of the cell cycle and is enriched in facultative heterochromatin, such as inactive X chromosomes in cycling cells. To track the dynamic changes of H4K20me1 in living cells, we have developed a genetically encoded modification-specific intracellular antibody (mintbody) probe that specifically binds to the modification. Here, we report the generation of knock-in mice in which the coding sequence of the mCherry-tagged version of the H4K20me1-mintbody is inserted into the Rosa26 locus. The knock-in mice, which ubiquitously expressed the H4K20me1-mintbody, developed normally and were fertile, indicating that the expression of the probe does not disturb the cell growth, development, or differentiation. Various tissues isolated from the knock-in mice exhibited nuclear fluorescence without the need for fixation. The H4K20me1-mintbody was enriched in inactive X chromosomes in developing embryos and in XY bodies during spermatogenesis. The knock-in mice will be useful for the histochemical analysis of H4K20me1 in any cell types.
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Affiliation(s)
- Yuko Sato
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan
| | - Maoko Takenoshita
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan
| | - Miku Ueoka
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan
| | - Jun Ueda
- Center for Genetic Analysis of Biological Responses, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Advanced Medical Science, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan
| | - Kazuo Yamagata
- Center for Genetic Analysis of Biological Responses, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan
- Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama, 649-6493, Japan
| | - Hiroshi Kimura
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan.
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8501, Japan.
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16
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Gu L, Fu Y, Li X. Roles of post-translational modifications of UHRF1 in cancer. Epigenetics Chromatin 2024; 17:15. [PMID: 38725075 PMCID: PMC11080273 DOI: 10.1186/s13072-024-00540-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/02/2024] [Indexed: 05/12/2024] Open
Abstract
UHRF1 as a member of RING-finger type E3 ubiquitin ligases family, is an epigenetic regulator with five structural domains. It has been involved in the regulation of a series of biological functions, such as DNA replication, DNA methylation, and DNA damage repair. Additionally, aberrant overexpression of UHRF1 has been observed in over ten cancer types, indicating that UHRF1 is a typical oncogene. The overexpression of UHRF1 repressed the transcription of such tumor-suppressor genes as CDKN2A, BRCA1, and CDH1 through DNMT1-mediated DNA methylation. In addition to the upstream transcription factors regulating gene transcription, post-translational modifications (PTMs) also contribute to abnormal overexpression of UHRF1 in cancerous tissues. The types of PTM include phosphorylation, acetylation, methylationand ubiquitination, which regulate protein stability, histone methyltransferase activity, intracellular localization and the interaction with binding partners. Recently, several novel PTM types of UHRF1 have been reported, but the detailed mechanisms remain unclear. This comprehensive review summarized the types of UHRF1 PTMs, as well as their biological functions. A deep understanding of these crucial mechanisms of UHRF1 is pivotal for the development of novel UHRF1-targeted anti-cancer therapeutic strategies in the future.
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Affiliation(s)
- Lili Gu
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Yongming Fu
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Xiong Li
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China.
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, Guangdong, China.
- NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
- School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
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17
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Cui X, Cao Q, Li F, Jing J, Liu Z, Yang X, Schwartz GJ, Yu L, Shi H, Shi H, Xue B. The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis. JCI Insight 2024; 9:e164771. [PMID: 38713533 PMCID: PMC11382888 DOI: 10.1172/jci.insight.164771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 05/01/2024] [Indexed: 05/09/2024] Open
Abstract
Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces - whereas Suv420h2 overexpression significantly increases - Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
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Affiliation(s)
- Xin Cui
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Qiang Cao
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Fenfen Li
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Jia Jing
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Zhixue Liu
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Xiaosong Yang
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Gary J Schwartz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Liqing Yu
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Huidong Shi
- Georgia Cancer Center and
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Hang Shi
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
| | - Bingzhong Xue
- Department of Biology, Georgia State University, Atlanta, Georgia, USA
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18
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Tong J, Chen X, Wang X, Men S, Liu Y, Sun X, Yan D, Wang L. Novel KMT5B variant associated with neurodevelopmental disorder in a Chinese family: A case report. Heliyon 2024; 10:e28686. [PMID: 38571636 PMCID: PMC10988039 DOI: 10.1016/j.heliyon.2024.e28686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024] Open
Abstract
Background We report here the clinical and genetic features of KMT5B-related neurodevelopmental disorder caused by a novel heterozygous frameshift variant in KMT5B in a Chinese family. Case presentation A 7-year-old Chinese boy with mild-to-moderate intellectual disability, significant language impairment, motor disability, and coordination difficulties presented to our hospital because he "could not speak and did not look at others." He was diagnosed with autism spectrum disorder previously owing to developmental delays in cognition, language expression, and understanding. The child also had variable nonspecific features including macrocephaly, wide button-hole space and nasal bridge, low ear, social behavior disorder, and foot deformities. Exome sequencing (ES) revealed that both the proband and his younger brother had inherited a novel heterozygous frameshift variant c.438_439ins[ASD; KT192064.1:1_310] of the KMT5B gene from their father. Bioinformatics analysis showed that the novel mutation affected the structure of the KMT5B pre-SET domain, mainly in the α-helix region. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this type of variant was eventually determined to be likely pathogenic (PVS1+PM2_P). Conclusions Our investigation expands the mutation spectrum of KMT5B to help us to better understand KMT5B-related neurodevelopmental disorder.
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Affiliation(s)
| | | | - Xin Wang
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Shuai Men
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Yuan Liu
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Xun Sun
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Dongmei Yan
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
| | - Leilei Wang
- Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu, China
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19
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Zeng B, Wan R, Chang K, Li J, Zhang X, Shi G, Ye D, Xu F. Lysine methyltransferase 5C increases the proliferation and metastatic abilities of clear cell renal cell carcinoma via aerobic glycolysis. Int J Oncol 2024; 64:45. [PMID: 38426605 PMCID: PMC10919755 DOI: 10.3892/ijo.2024.5633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 02/08/2024] [Indexed: 03/02/2024] Open
Abstract
Among all types of renal cancer, clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype and is associated with a high risk of metastasis and recurrence. Histone modifications regulate several biological processes that are fundamental to the development of cancer. Lysine methyltransferase 5C (KMT5C; also known as SUV420H2) is an epigenetic modifier responsible for the trimethylation of H4K20, which drives critical cellular events, including genome integrity, cell growth and epithelial‑mesenchymal transition (EMT), in various types of cancer. However, the role of KMT5C in ccRCC remains unclear. As such, the expression and function of KMT5C in ccRCC were investigated in the present study. KMT5C expression was significantly increased in ccRCC tissues compared with normal tissues (P<0.0001), and it was closely associated with the overall survival rate of patients with ccRCC. By establishing ccRCC cell lines with KMT5C expression knockdown, the role of KMT5C in the maintenance of aerobic glycolysis in ccRCC cells via the regulation of several vital glycolytic genes was identified. Additionally, KMT5C promoted the proliferation and EMT of ccRCC cells by controlling crucial EMT transcriptional factors. Together, these data suggested that KMT5C may act as an oncoprotein, guide molecular diagnosis, and shed light on novel drug development and therapeutic strategies for patients with ccRCC.
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Affiliation(s)
- Bohan Zeng
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Department of Urology, Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai 200003, P.R. China
| | - Runlan Wan
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Kun Chang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Jing Li
- Department of Respiratory and Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing 402260, P.R. China
| | - Xuanzhi Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Guohai Shi
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Fujiang Xu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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20
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Lossi L, Castagna C, Merighi A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. Int J Mol Sci 2024; 25:3881. [PMID: 38612690 PMCID: PMC11011998 DOI: 10.3390/ijms25073881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.
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Affiliation(s)
| | | | - Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (L.L.); (C.C.)
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21
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Blanc RS, Shah N, Salama NAS, Meng FW, Mousaei A, Yang BA, Aguilar CA, Chakkalakal JV, Onukwufor JO, Murphy PJ, Calvi L, Dirksen R. Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis. RESEARCH SQUARE 2024:rs.3.rs-3937628. [PMID: 38410478 PMCID: PMC10896381 DOI: 10.21203/rs.3.rs-3937628/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novoH4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.
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22
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Kashiwagi K, Yoshida J, Kimura H, Shinjo K, Kondo Y, Horie K. Mutation of the SWI/SNF complex component Smarce1 decreases nucleosome stability in embryonic stem cells and impairs differentiation. J Cell Sci 2024; 137:jcs260467. [PMID: 38357971 DOI: 10.1242/jcs.260467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 02/07/2024] [Indexed: 02/16/2024] Open
Abstract
The SWI/SNF chromatin remodeling complex consists of more than ten component proteins that form a large protein complex of >1 MDa. The catalytic proteins Smarca4 or Smarca2 work in concert with the component proteins to form a chromatin platform suitable for transcriptional regulation. However, the mechanism by which each component protein works synergistically with the catalytic proteins remains largely unknown. Here, we report on the function of Smarce1, a component of the SWI/SNF complex, through the phenotypic analysis of homozygous mutant embryonic stem cells (ESCs). Disruption of Smarce1 induced the dissociation of other complex components from the SWI/SNF complex. Histone binding to DNA was loosened in homozygous mutant ESCs, indicating that disruption of Smarce1 decreased nucleosome stability. Sucrose gradient sedimentation analysis suggested that there was an ectopic genomic distribution of the SWI/SNF complex upon disruption of Smarce1, accounting for the misregulation of chromatin conformations. Unstable nucleosomes remained during ESC differentiation, impairing the heterochromatin formation that is characteristic of the differentiation process. These results suggest that Smarce1 guides the SWI/SNF complex to the appropriate genomic regions to generate chromatin structures adequate for transcriptional regulation.
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Affiliation(s)
- Katsunobu Kashiwagi
- Department of Physiology II, Nara Medical University, Kashihara, Nara 634-8521, Japan
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Junko Yoshida
- Department of Physiology II, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hiroshi Kimura
- Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan
| | - Keiko Shinjo
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yutaka Kondo
- Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Kyoji Horie
- Department of Physiology II, Nara Medical University, Kashihara, Nara 634-8521, Japan
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23
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Yue B, Chen J, Bao T, Zhang Y, Yang L, Zhang Z, Wang Z, Zhu C. Chromosomal copy number amplification-driven Linc01711 contributes to gastric cancer progression through histone modification-mediated reprogramming of cholesterol metabolism. Gastric Cancer 2024; 27:308-323. [PMID: 38270815 DOI: 10.1007/s10120-023-01464-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/22/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND Chromosome gains or localized amplifications are frequently observed in human gastric cancer (GC) and are major causes of aberrant oncogene activation. However, the significance of long non-coding RNAs (LncRNAs) in the above process is largely unknown. METHODS The copy number aberrations (CNAs) data of GC samples were downloaded and analyzed from the TCGA database. qRT-PCR and fluorescence in situ hybridization were used to evaluate the expression of Linc01711 in GC. The effects of Linc01711 on GC progression were investigated through in vitro and in vivo assays. The mechanism of Linc01711 action was explored through transcriptome sequencing, chromatin immunoprecipitation sequencing, RNA immunoprecipitation, RNA pull-down and chromatin isolation by RNA purification (ChIRP) assays. RESULTS We report for the first time a novel DNA copy number amplification-driven LncRNA on chromosome 20q13, designated Linc01711 in human GC, which is highly associated with malignant features. Functionally, Linc01711 significantly accelerates the proliferation and metastasis of GC. Mechanistically, Linc01711 acts as a modular scaffold to promote the binding of histone acetyltransferase HBO1 and histone demethylase KDM9. By coordinating the localization of the HBO1/KDM9 complex, Linc01711 specifies the histone modification pattern on the target genes, such as LPCAT1, and consequently facilitates the cholesterol synthesis, thereby contributing to tumor progression. CONCLUSIONS Our findings suggest that copy number amplification-driven Linc01711 may serve as a promising prognostic predictor for GC patients and targeting Linc01711-related cholesterol metabolism pathway may be meaningful in anticancer strategies.
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Affiliation(s)
- Ben Yue
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Jianjun Chen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Tianshang Bao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yuanruohan Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Linxi Yang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Zizhen Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
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24
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Liu Z, Wang W, Xia Y, Gao Y, Wang Z, Li M, Presicce GA, An L, Du F. Overcoming the H4K20me3 epigenetic barrier improves somatic cell nuclear transfer reprogramming efficiency in mice. Cell Prolif 2024; 57:e13519. [PMID: 37322828 PMCID: PMC10771106 DOI: 10.1111/cpr.13519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/25/2023] [Accepted: 06/05/2023] [Indexed: 06/17/2023] Open
Abstract
Epigenetic reprogramming during fertilization and somatic cell nuclear transfer (NT) is required for cell plasticity and competent development. Here, we characterize the epigenetic modification pattern of H4K20me3, a repressive histone signature in heterochromatin, during fertilization and NT reprogramming. Importantly, the dynamic H4K20me3 signature identified during preimplantation development in fertilized embryos differed from NT and parthenogenetic activation (PA) embryos. In fertilized embryos, only maternal pronuclei carried the canonical H4K20me3 peripheral nucleolar ring-like signature. H4K20me3 disappeared at the 2-cell stage and reappeared in fertilized embryos at the 8-cell stage and in NT and PA embryos at the 4-cell stage. H4K20me3 intensity in 4-cell, 8-cell, and morula stages of fertilized embryos was significantly lower than in NT and PA embryos, suggesting aberrant regulation of H4K20me3 in PA and NT embryos. Indeed, RNA expression of the H4K20 methyltransferase Suv4-20h2 in 4-cell fertilized embryos was significantly lower than NT embryos. Knockdown of Suv4-20h2 in NT embryos rescued the H4K20me3 pattern similar to fertilized embryos. Compared to control NT embryos, knockdown of Suv4-20h2 in NT embryos improved blastocyst development ratios (11.1% vs. 30.5%) and full-term cloning efficiencies (0.8% vs. 5.9%). Upregulation of reprogramming factors, including Kdm4b, Kdm4d, Kdm6a, and Kdm6b, as well as ZGA-related factors, including Dux, Zscan4, and Hmgpi, was observed with Suv4-20h2 knockdown in NT embryos. Collectively, these are the first findings to demonstrate that H4K20me3 is an epigenetic barrier of NT reprogramming and begin to unravel the epigenetic mechanisms of H4K20 trimethylation in cell plasticity during natural reproduction and NT reprogramming in mice.
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Affiliation(s)
- Zhihui Liu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | - Weiguo Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | - Yuhan Xia
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | - Yuan Gao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | - Zhisong Wang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | - Mingyang Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
| | | | - Liyou An
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and TechnologyXinjiang UniversityUrumqiChina
| | - Fuliang Du
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life SciencesNanjing Normal UniversityNanjingChina
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25
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Jovanović B, Temko D, Stevens LE, Seehawer M, Fassl A, Murphy K, Anand J, Garza K, Gulvady A, Qiu X, Harper NW, Daniels VW, Xiao-Yun H, Ge JY, Alečković M, Pyrdol J, Hinohara K, Egri SB, Papanastasiou M, Vadhi R, Font-Tello A, Witwicki R, Peluffo G, Trinh A, Shu S, Diciaccio B, Ekram MB, Subedee A, Herbert ZT, Wucherpfennig KW, Letai AG, Jaffe JD, Sicinski P, Brown M, Dillon D, Long HW, Michor F, Polyak K. Heterogeneity and transcriptional drivers of triple-negative breast cancer. Cell Rep 2023; 42:113564. [PMID: 38100350 PMCID: PMC10842760 DOI: 10.1016/j.celrep.2023.113564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/05/2023] [Accepted: 11/22/2023] [Indexed: 12/17/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.
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Affiliation(s)
- Bojana Jovanović
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel Temko
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Laura E Stevens
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Marco Seehawer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Anne Fassl
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Katherine Murphy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Jayati Anand
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kodie Garza
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Anushree Gulvady
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nicholas W Harper
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Veerle W Daniels
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Huang Xiao-Yun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Jennifer Y Ge
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
| | - Maša Alečković
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Jason Pyrdol
- Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Kunihiko Hinohara
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Shawn B Egri
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
| | | | - Raga Vadhi
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Alba Font-Tello
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Robert Witwicki
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Guillermo Peluffo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Anne Trinh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Shaokun Shu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Benedetto Diciaccio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Muhammad B Ekram
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Ashim Subedee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Zachary T Herbert
- Department of Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kai W Wucherpfennig
- Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Anthony G Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Jacob D Jaffe
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA
| | - Deborah Dillon
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Henry W Long
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Franziska Michor
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
| | - Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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26
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Cordeiro-Spinetti E, Rothbart SB. Lysine methylation signaling in skeletal muscle biology: from myogenesis to clinical insights. Biochem J 2023; 480:1969-1986. [PMID: 38054592 DOI: 10.1042/bcj20230223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/07/2023]
Abstract
Lysine methylation signaling is well studied for its key roles in the regulation of transcription states through modifications on histone proteins. While histone lysine methylation has been extensively studied, recent discoveries of lysine methylation on thousands of non-histone proteins has broadened our appreciation for this small chemical modification in the regulation of protein function. In this review, we highlight the significance of histone and non-histone lysine methylation signaling in skeletal muscle biology, spanning development, maintenance, regeneration, and disease progression. Furthermore, we discuss potential future implications for its roles in skeletal muscle biology as well as clinical applications for the treatment of skeletal muscle-related diseases.
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Affiliation(s)
| | - Scott B Rothbart
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan 49503, U.S.A
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27
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Lin F, Zhang R, Shao W, Lei C, Ma M, Zhang Y, Wen Z, Li W. Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase. Cell Discov 2023; 9:120. [PMID: 38052811 DOI: 10.1038/s41421-023-00620-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/29/2023] [Indexed: 12/07/2023] Open
Abstract
Histone lysine methyltransferase SUV420H1, which is responsible for site-specific di-/tri-methylation of histone H4 lysine 20 (H4K20), has crucial roles in DNA-templated processes, including DNA replication, DNA damage repair, and chromatin compaction. Its mutations frequently occur in human cancers. Nucleosomes containing the histone variant H2A.Z enhance the catalytic activities of SUV420H1 on H4K20 di-methylation deposition, regulating early replication origins. However, the molecular mechanism by which SUV420H1 specifically recognizes and deposits H4K20 methyl marks on nucleosomes remains poorly understood. Here we report the cryo-electron microscopy structures of SUV420H1 associated with H2A-containing nucleosome core particles (NCPs), and H2A.Z-containing NCPs. We find that SUV420H1 makes extensive site-specific contacts with histone and DNA regions. SUV420H1 C-terminal domain recognizes the H2A-H2B acidic patch of NCPs through its two arginine anchors, thus enabling H4K20 insertion for catalysis specifically. We also identify important residues increasing the catalytic activities of SUV420H1 bound to H2A.Z NCPs. In vitro and in vivo functional analyses reveal that multiple disease-associated mutations at the interfaces are essential for its catalytic activity and chromatin state regulation. Together, our study provides molecular insights into the nucleosome-based recognition and methylation mechanisms of SUV420H1, and a structural basis for understanding SUV420H1-related human disease.
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Affiliation(s)
- Folan Lin
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Ruxin Zhang
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China
| | - Weihan Shao
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Cong Lei
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Mingxi Ma
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Ying Zhang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Zengqi Wen
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China.
| | - Wanqiu Li
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
- Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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28
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Wang C, Wang T, Li KJ, Hu LH, Li Y, Yu YZ, Xie T, Zhu S, Fu DJ, Wang Y, Zeng XZ, Liu FP, Chen H, Chen ZS, Feng NH, Liu J, Jiang Y, Zhao SC. SETD4 inhibits prostate cancer development by promoting H3K27me3-mediated NUPR1 transcriptional repression and cell cycle arrest. Cancer Lett 2023; 579:216464. [PMID: 37879429 DOI: 10.1016/j.canlet.2023.216464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/05/2023] [Accepted: 10/19/2023] [Indexed: 10/27/2023]
Abstract
The suppressor of variegation enhancer of zeste-trithorax (SET) domain methyltransferases have been reported to function as key regulators in multiple tumor types by catalyzing histone lysine methylation. Nevertheless, our understanding on the role of these lysine methyltransferases, including SETD4, in prostate cancer (PCa) remains limited. Hence, the specific role of SETD4 in PCa was investigated in this study. The expression of SETD4 in PCa cells and tissue samples was downregulated in PCa cells and tissue specimens, and decreased SETD4 expression led to inferior clinicopathological characteristics in patients with PCa. knockdown of SETD4 facilitated the proliferation of PCa cells and accelerated cell cycle progression. Mechanistically, SETD4 repressed NUPR1 transcription by methylating H3K27 to generate H3K27me3, subsequently inactivated Akt pathway and impeded the tumorigenesis of PCa. Our results highlight that SETD4 prevents the development of PCa by catalyzing the methylation of H3K27 and suppressing NUPR1 transcription, subsequently inactivating the Akt signaling pathway. The findings suggest the potential application of SETD4 in PCa prognosis and therapeutics.
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Affiliation(s)
- Chong Wang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Tao Wang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Urology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510900, China
| | - Kang-Jing Li
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ling-Hong Hu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yue Li
- Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yu-Zhong Yu
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China
| | - Tao Xie
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Sha Zhu
- Department of Urology, Jiangnan University Medical Center, Wuxi, 214002, China; Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, China
| | - Du-Jiang Fu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yang Wang
- Department of Urology, Jiangnan University Medical Center, Wuxi, 214002, China; Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, China
| | - Xian-Zi Zeng
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Feng-Ping Liu
- Department of Urology, Jiangnan University Medical Center, Wuxi, 214002, China; Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, China
| | - Hong Chen
- Luoyang Key Laboratory of Organic Functional Molecules, College of Food and Drug, Luoyang Normal University, Luoyang, Henan, 471934, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Ning-Han Feng
- Department of Urology, Jiangnan University Medical Center, Wuxi, 214002, China; Wuxi School of Medicine, Jiangnan University, Wuxi, 214002, China.
| | - Jinghua Liu
- Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Yong Jiang
- Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Shan-Chao Zhao
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China.
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29
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González J, Bosch-Presegué L, Marazuela-Duque A, Guitart-Solanes A, Espinosa-Alcantud M, Fernandez AF, Brown JP, Ausió J, Vazquez BN, Singh PB, Fraga MF, Vaquero A. A complex interplay between H2A.Z and HP1 isoforms regulates pericentric heterochromatin. Front Cell Dev Biol 2023; 11:1293122. [PMID: 38020886 PMCID: PMC10665487 DOI: 10.3389/fcell.2023.1293122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Pericentric heterochromatin (PCH) plays an essential role in the maintenance of genome integrity and alterations in PCH have been linked to cancer and aging. HP1 α, β, and γ, are hallmarks of constitutive heterochromatin that are thought to promote PCH structure through binding to heterochromatin-specific histone modifications and interaction with a wide range of factors. Among the less understood components of PCH is the histone H2A variant H2A.Z, whose role in the organization and maintenance of PCH is poorly defined. Here we show that there is a complex interplay between H2A.Z and HP1 isoforms in PCH. While the loss of HP1α results in the accumulation of H2A.Z.1 in PCH, which is associated with a significant decrease in its mobile fraction, H2A.Z.1 binds preferentially to HP1β in these regions. Of note, H2A.Z.1 downregulation results in increased heterochromatinization and instability of PCH, reflected by accumulation of the major epigenetic hallmarks of heterochromatin in these regions and increased frequency of chromosome aberrations related to centromeric/pericentromeric defects. Our studies support a role for H2A.Z in genome stability and unveil a key role of H2A.Z in the regulation of heterochromatin-specific epigenetic modifications through a complex interplay with the HP1 isoforms.
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Affiliation(s)
- Jessica González
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Laia Bosch-Presegué
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Tissue Repair and Regeneration Laboratory (TR2Lab), Institut de Recerca I Innovació en Ciències de La Vida i de La Salut a La Catalunya Central (IrisCC), Barcelona, Spain
| | - Anna Marazuela-Duque
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Anna Guitart-Solanes
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - María Espinosa-Alcantud
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Agustín F. Fernandez
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), El Entrego, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), Madrid, Spain
| | - Jeremy P. Brown
- Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, The Hammersmith Hospital, London, United Kingdom
| | - Juan Ausió
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Berta N. Vazquez
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Cytology and Histology Unit. Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Prim B. Singh
- Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Mario F. Fraga
- Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), El Entrego, Spain
- Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain
- Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
- Spanish Biomedical Research Network in Rare Diseases (CIBERER), Madrid, Spain
| | - Alejandro Vaquero
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
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30
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Hamali B, Amine AAA, Al-Sady B. Regulation of the heterochromatin spreading reaction by trans-acting factors. Open Biol 2023; 13:230271. [PMID: 37935357 PMCID: PMC10645111 DOI: 10.1098/rsob.230271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/03/2023] [Indexed: 11/09/2023] Open
Abstract
Heterochromatin is a gene-repressive protein-nucleic acid ultrastructure that is initially nucleated by DNA sequences. However, following nucleation, heterochromatin can then propagate along the chromatin template in a sequence-independent manner in a reaction termed spreading. At the heart of this process are enzymes that deposit chemical information on chromatin, which attracts the factors that execute chromatin compaction and transcriptional or co/post-transcriptional gene silencing. Given that these enzymes deposit guiding chemical information on chromatin they are commonly termed 'writers'. While the processes of nucleation and central actions of writers have been extensively studied and reviewed, less is understood about how the spreading process is regulated. We discuss how the chromatin substrate is prepared for heterochromatic spreading, and how trans-acting factors beyond writer enzymes regulate it. We examine mechanisms by which trans-acting factors in Suv39, PRC2, SETDB1 and SIR writer systems regulate spreading of the respective heterochromatic marks across chromatin. While these systems are in some cases evolutionarily and mechanistically quite distant, common mechanisms emerge which these trans-acting factors exploit to tune the spreading reaction.
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Affiliation(s)
- Bulut Hamali
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- The G. W. Hooper Foundation, San Francisco, CA 94143, USA
- College of Dentistry, The Ohio State University, Columbus, OH, USA
| | - Ahmed A A Amine
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- The G. W. Hooper Foundation, San Francisco, CA 94143, USA
| | - Bassem Al-Sady
- Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- The G. W. Hooper Foundation, San Francisco, CA 94143, USA
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31
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Kumar P, Brooks HL. Sex-specific epigenetic programming in renal fibrosis and inflammation. Am J Physiol Renal Physiol 2023; 325:F578-F594. [PMID: 37560775 PMCID: PMC11550885 DOI: 10.1152/ajprenal.00091.2023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/18/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023] Open
Abstract
The growing prevalence of hypertension, heart disease, diabetes, and obesity along with an aging population is leading to a higher incidence of renal diseases in society. Chronic kidney disease (CKD) is characterized mainly by persistent inflammation, fibrosis, and gradual loss of renal function leading to renal failure. Sex is a known contributor to the differences in incidence and progression of CKD. Epigenetic programming is an essential regulator of renal physiology and is critically involved in the pathophysiology of renal injury and fibrosis. Epigenetic signaling integrates intrinsic and extrinsic signals onto the genome, and various environmental and hormonal stimuli, including sex hormones, which regulate gene expression and downstream cellular responses. The most extensively studied epigenetic alterations that play a critical role in renal damage include histone modifications and DNA methylation. Notably, these epigenetic alterations are reversible, making them candidates for potential therapeutic targets for the treatment of renal diseases. Here, we will summarize the current knowledge on sex differences in epigenetic modulation of renal fibrosis and inflammation and highlight some possible epigenetic therapeutic strategies for CKD treatment.
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Affiliation(s)
- Prerna Kumar
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
| | - Heddwen L Brooks
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, United States
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32
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Xu Y, He Z, Du J, Chen Z, Creemers JWM, Wang B, Li F, Wang Y. Epigenetic modulations of immune cells: from normal development to tumor progression. Int J Biol Sci 2023; 19:5120-5144. [PMID: 37928272 PMCID: PMC10620821 DOI: 10.7150/ijbs.88327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/21/2023] [Indexed: 11/07/2023] Open
Abstract
The dysfunction of immune cell development often impairs immunological homeostasis, thus causing various human diseases. Accumulating evidence shows that the development of different immune cells from hematopoietic stem cells are highly fine-tuned by different epigenetic mechanisms including DNA methylation, histone modifications, chromatin remodeling and RNA-related regulations. Understanding how epigenetic regulators modulate normal development of immune cells contributes to the identification of new strategies for various diseases. Here, we review recent advances suggesting that epigenetic modulations can orchestrate immune cell development and functions through their impact on critical gene expression. We also discuss the aberrations of epigenetic modulations in immune cells that influence tumor progression, and the fact that underlying mechanisms affect how epigenetic drugs interfere with tumor progression in the clinic.
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Affiliation(s)
- Yuanchun Xu
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
- Department of nursing, Daping Hospital, Army Medical University, Chongqing, China
| | - Zongsheng He
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Du
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Ziqiang Chen
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | | | - Bin Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Fan Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Yaling Wang
- Department of nursing, Daping Hospital, Army Medical University, Chongqing, China
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33
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Lu-Culligan WJ, Connor LJ, Xie Y, Ekundayo BE, Rose BT, Machyna M, Pintado-Urbanc AP, Zimmer JT, Vock IW, Bhanu NV, King MC, Garcia BA, Bleichert F, Simon MD. Acetyl-methyllysine marks chromatin at active transcription start sites. Nature 2023; 622:173-179. [PMID: 37731000 PMCID: PMC10845139 DOI: 10.1038/s41586-023-06565-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 08/23/2023] [Indexed: 09/22/2023]
Abstract
Lysine residues in histones and other proteins can be modified by post-translational modifications that encode regulatory information1. Lysine acetylation and methylation are especially important for regulating chromatin and gene expression2-4. Pathways involving these post-translational modifications are targets for clinically approved therapeutics to treat human diseases. Lysine methylation and acetylation are generally assumed to be mutually exclusive at the same residue. Here we report cellular lysine residues that are both methylated and acetylated on the same side chain to form Nε-acetyl-Nε-methyllysine (Kacme). We show that Kacme is found on histone H4 (H4Kacme) across a range of species and across mammalian tissues. Kacme is associated with marks of active chromatin, increased transcriptional initiation and is regulated in response to biological signals. H4Kacme can be installed by enzymatic acetylation of monomethyllysine peptides and is resistant to deacetylation by some HDACs in vitro. Kacme can be bound by chromatin proteins that recognize modified lysine residues, as we demonstrate with the crystal structure of acetyllysine-binding protein BRD2 bound to a histone H4Kacme peptide. These results establish Kacme as a cellular post-translational modification with the potential to encode information distinct from methylation and acetylation alone and demonstrate that Kacme has all the hallmarks of a post-translational modification with fundamental importance to chromatin biology.
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Affiliation(s)
- William J Lu-Culligan
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Leah J Connor
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Yixuan Xie
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
| | - Babatunde E Ekundayo
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
| | - Brendan T Rose
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Martin Machyna
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Andreas P Pintado-Urbanc
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Joshua T Zimmer
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Isaac W Vock
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Natarajan V Bhanu
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
| | - Megan C King
- Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA
| | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
| | - Franziska Bleichert
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
| | - Matthew D Simon
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA.
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA.
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34
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Möller M, Ridenour JB, Wright DF, Martin FA, Freitag M. H4K20me3 is important for Ash1-mediated H3K36me3 and transcriptional silencing in facultative heterochromatin in a fungal pathogen. PLoS Genet 2023; 19:e1010945. [PMID: 37747878 PMCID: PMC10553808 DOI: 10.1371/journal.pgen.1010945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/05/2023] [Accepted: 08/30/2023] [Indexed: 09/27/2023] Open
Abstract
Facultative heterochromatin controls development and differentiation in many eukaryotes. In metazoans, plants, and many filamentous fungi, facultative heterochromatin is characterized by transcriptional repression and enrichment with nucleosomes that are trimethylated at histone H3 lysine 27 (H3K27me3). While loss of H3K27me3 results in derepression of transcriptional gene silencing in many species, additional up- and downstream layers of regulation are necessary to mediate control of transcription in chromosome regions enriched with H3K27me3. Here, we investigated the effects of one histone mark on histone H4, namely H4K20me3, in the fungus Zymoseptoria tritici, a globally important pathogen of wheat. Deletion of kmt5, the gene encoding the sole methyltransferase responsible for H4K20 methylation, resulted in global derepression of transcription, especially in regions of facultative heterochromatin. Derepression in the absence of H4K20me3 not only affected known genes but also a large number of novel, previously undetected transcripts generated from regions of facultative heterochromatin on accessory chromosomes. Transcriptional activation in kmt5 deletion strains was accompanied by a complete loss of Ash1-mediated H3K36me3 and chromatin reorganization affecting H3K27me3 and H3K4me2 distribution in regions of facultative heterochromatin. Strains with H4K20L, M or Q mutations in the single histone H4 gene of Z. tritici recapitulated these chromatin changes, suggesting that H4K20me3 is important for Ash1-mediated H3K36me3. The ∆kmt5 mutants we obtained were more sensitive to genotoxic stressors than wild type and both, ∆kmt5 and ∆ash1, showed greatly increased rates of accessory chromosome loss. Taken together, our results provide insights into an unsuspected mechanism involved in the assembly and maintenance of facultative heterochromatin.
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Affiliation(s)
- Mareike Möller
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - John B. Ridenour
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - Devin F. Wright
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - Faith A. Martin
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - Michael Freitag
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
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35
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Agredo A, Kasinski AL. Histone 4 lysine 20 tri-methylation: a key epigenetic regulator in chromatin structure and disease. Front Genet 2023; 14:1243395. [PMID: 37671044 PMCID: PMC10475950 DOI: 10.3389/fgene.2023.1243395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/07/2023] [Indexed: 09/07/2023] Open
Abstract
Chromatin is a vital and dynamic structure that is carefully regulated to maintain proper cell homeostasis. A great deal of this regulation is dependent on histone proteins which have the ability to be dynamically modified on their tails via various post-translational modifications (PTMs). While multiple histone PTMs are studied and often work in concert to facilitate gene expression, here we focus on the tri-methylation of histone H4 on lysine 20 (H4K20me3) and its function in chromatin structure, cell cycle, DNA repair, and development. The recent studies evaluated in this review have shed light on how H4K20me3 is established and regulated by various interacting partners and how H4K20me3 and the proteins that interact with this PTM are involved in various diseases. Through analyzing the current literature on H4K20me3 function and regulation, we aim to summarize this knowledge and highlights gaps that remain in the field.
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Affiliation(s)
- Alejandra Agredo
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
- Purdue Life Sciences Interdisciplinary Program (PULSe), Purdue University, West Lafayette, IN, United States
| | - Andrea L. Kasinski
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, United States
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36
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Abini-Agbomson S, Gretarsson K, Shih RM, Hsieh L, Lou T, De Ioannes P, Vasilyev N, Lee R, Wang M, Simon MD, Armache JP, Nudler E, Narlikar G, Liu S, Lu C, Armache KJ. Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. Mol Cell 2023; 83:2872-2883.e7. [PMID: 37595555 DOI: 10.1016/j.molcel.2023.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/12/2023] [Accepted: 07/20/2023] [Indexed: 08/20/2023]
Abstract
SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.
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Affiliation(s)
- Stephen Abini-Agbomson
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Kristjan Gretarsson
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Rochelle M Shih
- Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, NY, USA
| | - Laura Hsieh
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Tracy Lou
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Pablo De Ioannes
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Nikita Vasilyev
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Rachel Lee
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Miao Wang
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Matthew D Simon
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
| | - Jean-Paul Armache
- Department of Biochemistry and Molecular Biology and the Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Evgeny Nudler
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Geeta Narlikar
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Shixin Liu
- Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, NY, USA
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Karim-Jean Armache
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
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37
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Salimi F, Asadikaram G, Ashrafi MR, Zeynali Nejad H, Abolhassani M, Abbasi-Jorjandi M, Sanjari M. Organochlorine pesticides and epigenetic alterations in thyroid tumors. Front Endocrinol (Lausanne) 2023; 14:1130794. [PMID: 37560303 PMCID: PMC10409498 DOI: 10.3389/fendo.2023.1130794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 07/03/2023] [Indexed: 08/11/2023] Open
Abstract
Purpose Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients. Methods OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis. Results Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, P=0.001) and P16 (OR=5.65, P<0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (P<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, P<0.001) and H4K16 (OR=6.03, P<0.001) acetylation. Conclusion The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.
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Affiliation(s)
- Fouzieh Salimi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences Kerman University of Medical Sciences, Kerman, Iran
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical sciences, Kerman, Iran
| | - Gholamreza Asadikaram
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical sciences, Kerman, Iran
| | - Mohammad Reza Ashrafi
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical sciences, Kerman, Iran
| | - Hamid Zeynali Nejad
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Surgery, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Moslem Abolhassani
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical sciences, Kerman, Iran
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mojtaba Abbasi-Jorjandi
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical sciences, Kerman, Iran
| | - Mojgan Sanjari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences Kerman University of Medical Sciences, Kerman, Iran
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Angerilli A, Tait J, Berges J, Shcherbakova I, Pokrovsky D, Schauer T, Smialowski P, Hsam O, Mentele E, Nicetto D, Rupp RA. The histone H4K20 methyltransferase SUV4-20H1/KMT5B is required for multiciliated cell differentiation in Xenopus. Life Sci Alliance 2023; 6:e202302023. [PMID: 37116939 PMCID: PMC10147948 DOI: 10.26508/lsa.202302023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/18/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023] Open
Abstract
H4 lysine 20 dimethylation (H4K20me2) is the most abundant histone modification in vertebrate chromatin. It arises from sequential methylation of unmodified histone H4 proteins by the mono-methylating enzyme PR-SET7/KMT5A, followed by conversion to the dimethylated state by SUV4-20H (KMT5B/C) enzymes. We have blocked the deposition of this mark by depleting Xenopus embryos of SUV4-20H1/H2 methyltransferases. In the larval epidermis, this results in a severe loss of cilia in multiciliated cells (MCC), a key component of mucociliary epithelia. MCC precursor cells are correctly specified, amplify centrioles, but ultimately fail in ciliogenesis because of the perturbation of cytoplasmic processes. Genome-wide transcriptome profiling reveals that SUV4-20H1/H2-depleted ectodermal explants preferentially down-regulate the expression of several hundred ciliogenic genes. Further analysis demonstrated that knockdown of SUV4-20H1 alone is sufficient to generate the MCC phenotype and that its catalytic activity is needed for axoneme formation. Overexpression of the H4K20me1-specific histone demethylase PHF8/KDM7B also rescues the ciliogenic defect in a significant manner. Taken together, this indicates that the conversion of H4K20me1 to H4K20me2 by SUV4-20H1 is critical for the formation of cilia tufts.
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Affiliation(s)
- Alessandro Angerilli
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Janet Tait
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Julian Berges
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
- Sektion Pädiatrische Pneumologie und Allergologie und Mukoviszidose-Zentrum, Universitäts-Klinikum Heidelberg, Heidelberg, Germany
| | - Irina Shcherbakova
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Daniil Pokrovsky
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Tamas Schauer
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Pawel Smialowski
- Institute for Stem Cell Research, Helmholtz Centre Munich, Neuherberg, Germany
- Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Ohnmar Hsam
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
- Klinik und Poliklinik für Neurologie der Universität Regensburg, Regensburg, Germany
| | - Edith Mentele
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Dario Nicetto
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
- Ambys Medicines, South San Francisco, CA, USA
| | - Ralph Aw Rupp
- Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
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Zeng Y, Ma G, Cai F, Wang P, Liang H, Zhang R, Deng J, Liu Y. SMYD3 drives the proliferation in gastric cancer cells via reducing EMP1 expression in an H4K20me3-dependent manner. Cell Death Dis 2023; 14:386. [PMID: 37386026 PMCID: PMC10310787 DOI: 10.1038/s41419-023-05907-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/01/2023]
Abstract
Protein lysine methyltransferase SET and MYND domain-containing 3 (SMYD3) is aberrantly expressed in various cancer settings. The mechanisms that SMYD3 activates the expression of critical pro-tumoral genes in an H3K4me3-dependent manner have been well described in previous reports. Besides H3K4me3, H4K20me3 is another catalytic product of SMYD3, however it is a transcriptionally repressive hallmark. Since it is not clear that how SMYD3-elicited transcriptionally repressive program functions in cancer, we used gastric cancer (GC) as a model to investigate the roles of SMYD3-H4K20me3. Herein, online bioinformatics tools, quantitative PCR, western blotting and immunohistochemistry assays demonstrated that SMYD3 expression was markedly increased in GC tissues from our institutional and The Cancer Genome Atlas (TCGA) cohort. Additionally, aberrantly increased SMYD3 expression was closely associated with aggressive clinical characteristics and poor prognosis. Depletion of endogenous SMYD3 expression using shRNAs significantly attenuates the proliferation in GC cells and Akt signaling pathway in vitro and in vivo. Mechanistically, chromatin immunoprecipitation (ChIP) assay showed that SMYD3 epigenetically repressed the expression of epithelial membrane protein 1 (EMP1) in an H4K20me3-dependent manner. Gain-of-function and rescue experiments validated that EMP1 inhibited the propagation of GC cells and reduced p-Akt (S473) level. Based on these data, pharmaceutical inhibition of SMYD3 activity using the small inhibitor BCI-121 deactivated Akt signaling pathway in GC cells and further impaired the cellular viability in vitro and in vivo. Together, these results demonstrate that SMYD3 promotes the proliferation in GC cells and may be a valid target for therapeutic intervention of patients with GC.
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Affiliation(s)
- Yi Zeng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350000, Fujian, PR China
| | - Gang Ma
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
- Department of Biochemistry and Molecular Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300060, PR China
| | - Pengliang Wang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China
| | - Han Liang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China.
| | - Yong Liu
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China.
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40
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Baxter AE, Huang H, Giles JR, Chen Z, Wu JE, Drury S, Dalton K, Park SL, Torres L, Simone BW, Klapholz M, Ngiow SF, Freilich E, Manne S, Alcalde V, Ekshyyan V, Berger SL, Shi J, Jordan MS, Wherry EJ. The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8 + T cells. Immunity 2023; 56:1320-1340.e10. [PMID: 37315535 DOI: 10.1016/j.immuni.2023.05.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 02/28/2023] [Accepted: 05/11/2023] [Indexed: 06/16/2023]
Abstract
CD8+ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8+ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1+ progenitor Tex cells to more differentiated TCF-1- Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.
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Affiliation(s)
- Amy E Baxter
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Hua Huang
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Josephine R Giles
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Zeyu Chen
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jennifer E Wu
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Sydney Drury
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Katherine Dalton
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Simone L Park
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Leonel Torres
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Brandon W Simone
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Max Klapholz
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Shin Foong Ngiow
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Elizabeth Freilich
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Sasikanth Manne
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Victor Alcalde
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Viktoriya Ekshyyan
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Shelley L Berger
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Junwei Shi
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| | - Martha S Jordan
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| | - E John Wherry
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Hussain S, Sadouni N, van Essen D, Dao LTM, Ferré Q, Charbonnier G, Torres M, Gallardo F, Lecellier CH, Sexton T, Saccani S, Spicuglia S. Short tandem repeats are important contributors to silencer elements in T cells. Nucleic Acids Res 2023; 51:4845-4866. [PMID: 36929452 PMCID: PMC10250210 DOI: 10.1093/nar/gkad187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/26/2023] [Accepted: 03/15/2023] [Indexed: 03/18/2023] Open
Abstract
The action of cis-regulatory elements with either activation or repression functions underpins the precise regulation of gene expression during normal development and cell differentiation. Gene activation by the combined activities of promoters and distal enhancers has been extensively studied in normal and pathological contexts. In sharp contrast, gene repression by cis-acting silencers, defined as genetic elements that negatively regulate gene transcription in a position-independent fashion, is less well understood. Here, we repurpose the STARR-seq approach as a novel high-throughput reporter strategy to quantitatively assess silencer activity in mammals. We assessed silencer activity from DNase hypersensitive I sites in a mouse T cell line. Identified silencers were associated with either repressive or active chromatin marks and enriched for binding motifs of known transcriptional repressors. CRISPR-mediated genomic deletions validated the repressive function of distinct silencers involved in the repression of non-T cell genes and genes regulated during T cell differentiation. Finally, we unravel an association of silencer activity with short tandem repeats, highlighting the role of repetitive elements in silencer activity. Our results provide a general strategy for genome-wide identification and characterization of silencer elements.
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Affiliation(s)
- Saadat Hussain
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Nori Sadouni
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Dominic van Essen
- Institute for Research on Cancer and Ageing, IRCAN, 06107 Nice, France
| | - Lan T M Dao
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Quentin Ferré
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Guillaume Charbonnier
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Magali Torres
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Frederic Gallardo
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
| | - Charles-Henri Lecellier
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- LIRMM, University of Montpellier, CNRS, Montpellier, France
| | - Tom Sexton
- Institut de Génétique et de Biologie Moléculaire et Cellulaire – IGBMC (CNRS UMR 7104, INSERM U1258, Université de Strasbourg), 67404 Illkirch, France
| | - Simona Saccani
- Institute for Research on Cancer and Ageing, IRCAN, 06107 Nice, France
| | - Salvatore Spicuglia
- Aix-Marseille University, Inserm, TAGC, UMR1090, Marseille, France
- Equipe Labélisée Ligue Contre le Cancer, Marseille, France
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Shen J, Wang Q, Mao Y, Gao W, Duan S. Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies. MedComm (Beijing) 2023; 4:e288. [PMID: 37256211 PMCID: PMC10225743 DOI: 10.1002/mco2.288] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 04/25/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling-targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor-promoting role by blocking the mitochondria-dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.
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Affiliation(s)
- Jinze Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouZhejiangChina
| | - Qurui Wang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouZhejiangChina
| | - Yunan Mao
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouZhejiangChina
| | - Wei Gao
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouZhejiangChina
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang ProvinceSchool of MedicineHangzhou City UniversityHangzhouZhejiangChina
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Wang Y, Yu Y, Yang W, Wu L, Yang Y, Lu Q, Zhou J. SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence. Stem Cells Int 2023; 2023:7367854. [PMID: 37274024 PMCID: PMC10239305 DOI: 10.1155/2023/7367854] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 04/23/2023] [Accepted: 05/08/2023] [Indexed: 06/06/2023] Open
Abstract
Increasing evidence indicates that quiescent cancer stem cells (CSCs) are a root cause of chemoresistance. SET domain-containing protein 4 (SETD4) epigenetically regulates cell quiescence in breast cancer stem cells (BCSCs), and SETD4-positive BCSCs are chemoradioresistant. However, the role of SETD4 in chemoresistance, tumor progression, and prognosis in nonsmall cell lung cancer (NSCLC) patients is unclear. Here, SETD4-positive cells were identified as quiescent lung cancer stem cells (qLCSCs) since they expressed high levels of ALDH1 and CD133 and low levels of Ki67. SETD4 expression was significantly higher in advanced-stage NSCLC tissues than in early-stage NSCLC tissues and significantly higher in samples from the chemoresistant group than in those from the chemosensitive group. Patients with high SETD4 expression had shorter progression-free survival (PFS) times than those with low SETD4 expression. SETD4 facilitated heterochromatin formation via H4K20me3, thereby leading to cell quiescence. RNA-seq analysis showed upregulation of genes involved in cell proliferation, glucose metabolism, and PI3K-AKT signaling in activated qLCSCs (A-qLCSCs) compared with qLCSCs. In addition, SETD4 overexpression facilitated PTEN-mediated inhibition of the PI3K-mTOR pathway. In summary, SETD4 confers chemoresistance, tumor progression, and a poor prognosis by regulating CSCs in NSCLC patients.
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Affiliation(s)
- Yuehong Wang
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuman Yu
- Department of Geriatrics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Weijun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Linying Wu
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yaoshun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qianyun Lu
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianying Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Monte-Serrano E, Morejón-García P, Campillo-Marcos I, Campos-Díaz A, Navarro-Carrasco E, Lazo PA. The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase. Epigenetics Chromatin 2023; 16:18. [PMID: 37179361 PMCID: PMC10182654 DOI: 10.1186/s13072-023-00494-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A. METHODS The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells. RESULTS Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1. CONCLUSIONS The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.
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Affiliation(s)
- Eva Monte-Serrano
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain
| | - Patricia Morejón-García
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain
| | - Ignacio Campillo-Marcos
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain
| | - Aurora Campos-Díaz
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain
| | - Elena Navarro-Carrasco
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain
| | - Pedro A Lazo
- Molecular Mechanisms of Cancer Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, 37007, Salamanca, Spain.
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain.
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Abini-Agbomson S, Gretarsson K, Shih RM, Hsieh L, Lou T, De Ioannes P, Vasilyev N, Lee R, Wang M, Simon M, Armache JP, Nudler E, Narlikar G, Liu S, Lu C, Armache KJ. Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.17.533220. [PMID: 36993485 PMCID: PMC10055266 DOI: 10.1101/2023.03.17.533220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The intricate regulation of chromatin plays a key role in controlling genome architecture and accessibility. Histone lysine methyltransferases regulate chromatin by catalyzing the methylation of specific histone residues but are also hypothesized to have equally important non-catalytic roles. SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation, and is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes suggesting the enzyme likely has uncharacterized non-catalytic activities. To characterize the catalytic and non-catalytic mechanisms SUV420H1 uses to modify chromatin, we determined cryo- EM structures of SUV420H1 complexes with nucleosomes containing histone H2A or its variant H2A.Z. Our structural, biochemical, biophysical, and cellular analyses reveal how both SUV420H1 recognizes its substrate and H2A.Z stimulates its activity, and show that SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from histone octamer. We hypothesize that this detachment increases DNA accessibility to large macromolecular complexes, a prerequisite for DNA replication and repair. We also show that SUV420H1 can promote chromatin condensates, another non-catalytic role that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.
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Affiliation(s)
- Stephen Abini-Agbomson
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Kristjan Gretarsson
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Rochelle M. Shih
- Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, NY, USA
| | - Laura Hsieh
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Tracy Lou
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Pablo De Ioannes
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Nikita Vasilyev
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Rachel Lee
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Miao Wang
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Matthew Simon
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
| | - Jean-Paul Armache
- Department of Biochemistry and Molecular Biology and the Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Evgeny Nudler
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Geeta Narlikar
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Shixin Liu
- Laboratory of Nanoscale Biophysics and Biochemistry, The Rockefeller University, New York, NY, USA
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Karim-Jean Armache
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Lead contact
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Li ASM, Homsi C, Bonneil E, Thibault P, Verreault A, Vedadi M. Histone H4K20 monomethylation enables recombinant nucleosome methylation by PRMT1 in vitro. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194922. [PMID: 36822575 DOI: 10.1016/j.bbagrm.2023.194922] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/23/2023]
Abstract
Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to specific arginine residues of histones and nonhistone proteins. There are nine members in the PRMT family (PRMT1 to PRMT9), and PRMT1 is a dominant member catalyzing majority of arginine methylation in the cell. However, none of the PRMTs is active with recombinant nucleosome as substrate in vitro. Here, we report the discovery of the first in class novel crosstalk between histone H4 lysine 20 (H4K20) monomethylation on nucleosome by SETD8 and histone H4 arginine 3 (H4R3) methylation by PRMT1 in vitro. Full kinetic characterization and mass spectrometry analysis indicated that PRMT1 is only active with recombinant nucleosomes monomethylated at H4K20 by SETD8. These data suggests that the level of activity of PRMT1 could potentially be regulated selectively by SETD8 in various pathways, providing a new approach for discovery of selective regulators of PRMT1 activity.
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Affiliation(s)
- Alice Shi Ming Li
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Charles Homsi
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Eric Bonneil
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada; Department of Chemistry, Université de Montréal, Montréal, Quebec H3C 3J7, Canada
| | - Alain Verreault
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, QC, Canada
| | - Masoud Vedadi
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
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Roy A, Niharika, Chakraborty S, Mishra J, Singh SP, Patra SK. Mechanistic aspects of reversible methylation modifications of arginine and lysine of nuclear histones and their roles in human colon cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:261-302. [PMID: 37019596 DOI: 10.1016/bs.pmbts.2023.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Developmental proceedings and maintenance of cellular homeostasis are regulated by the precise orchestration of a series of epigenetic events that eventually control gene expression. DNA methylation and post-translational modifications (PTMs) of histones are well-characterized epigenetic events responsible for fine-tuning gene expression. PTMs of histones bear molecular logic of gene expression at chromosomal territory and have become a fascinating field of epigenetics. Nowadays, reversible methylation on histone arginine and lysine is gaining increasing attention as a significant PTM related to reorganizing local nucleosomal structure, chromatin dynamics, and transcriptional regulation. It is now well-accepted and reported that histone marks play crucial roles in colon cancer initiation and progression by encouraging abnormal epigenomic reprogramming. It is becoming increasingly clear that multiple PTM marks at the N-terminal tails of the core histones cross-talk with one another to intricately regulate DNA-templated biological processes such as replication, transcription, recombination, and damage repair in several malignancies, including colon cancer. These functional cross-talks provide an additional layer of message, which spatiotemporally fine-tunes the overall gene expression regulation. Nowadays, it is evident that several PTMs instigate colon cancer development. How colon cancer-specific PTM patterns or codes are generated and how they affect downstream molecular events are uncovered to some extent. Future studies would address more about epigenetic communication, and the relationship between histone modification marks to define cellular functions in depth. This chapter will comprehensively highlight the importance of histone arginine and lysine-based methylation modifications and their functional cross-talk with other histone marks from the perspective of colon cancer development.
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Li X, Qian Y, Shen W, Zhang S, Han H, Zhang Y, Liu S, Lv S, Zhang X. Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury. Mediators Inflamm 2023; 2023:4420592. [PMID: 36936537 PMCID: PMC10023234 DOI: 10.1155/2023/4420592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/10/2022] [Accepted: 11/24/2022] [Indexed: 03/12/2023] Open
Abstract
Background Spinal cord injury (SCI) is a common injury of the central nervous system (CNS), and astrocytes are relatively abundant glial cells in the CNS that impairs the recovery of motor function after SCI. It was confirmed that the oxidative stress of mitochondria leads to the accumulation of reactive oxygen species (ROS) in cells, which plays a key role in the motor function of astrocytes. However, the mechanism by which oxidative stress affects astrocyte motility after SCI is still unexplained. Therefore, this study investigated the influence of SET8-regulated oxidative stress on astrocyte autophagy levels after SCI in rats and the potential mechanisms of action. Methods We used real-time quantitative PCR, western blotting, and immunohistochemical staining to analyze SET8, Keap1, and Nrf2 expression at the cellular level and in SCI tissues. ChIP to detect H4K20me1 enrichment in the Keap1 promoter region under OE-SET8 (overexpression of SET8) conditions. Western blotting was used to assess the expression of signature proteins of astrocytes, proteins associated with autophagy, proteins associated with glial scar formation, reactive oxygen species (ROS) levels in cells using DHE staining, and astrocyte number, morphological alterations, and induction of glial scar formation processes using immunofluorescence. In addition, the survival rate of neurons after SCI in rats was examined by using NiSSl staining. Results OE-SET8 upregulates the enrichment of H4K20me1 in Keap1, inhibits Keap1 expression, activates the Nrf2-ARE signaling pathway to suppress ROS accumulation, inhibits oxidative stress-induced autophagy and glial scar formation in astrocytes, and leads to reduced neuronal loss, which promoted the recovery and improvement of motor function after SCI in rats. Conclusion Overexpression of SET8 alleviated oxidative stress by regulating Keap1/Nrf2/ARE, inhibited astrocyte autophagy levels, and reduced glial scar formation as well as neuronal loss, thereby promoting improved recovery of motor function after SCI. Thus, the SET8/H4K20me1 regulatory function may be a promising cellular therapeutic intervention point after SCI.
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Affiliation(s)
- Xin Li
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Yan Qian
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Wanling Shen
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Shiying Zhang
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Hui Han
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Yu Zhang
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Shuangmei Liu
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Shaokun Lv
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
| | - Xiuying Zhang
- Rehabilitation Medicine of Qujing No. 1 Hospital, Qujing, 655000 Yunnan, China
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Barsoum M, Stenzel AT, Bochyńska A, Kuo CC, Tsompanidis A, Sayadi-Boroujeni R, Bussmann P, Lüscher-Firzlaff J, Costa IG, Lüscher B. Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes reduces chromatin accessibility at promoters. Sci Rep 2022; 12:21506. [PMID: 36513698 PMCID: PMC9747801 DOI: 10.1038/s41598-022-25881-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022] Open
Abstract
Changes in gene expression programs are intimately linked to cell fate decisions. Post-translational modifications of core histones contribute to control gene expression. Methylation of lysine 4 of histone H3 (H3K4) correlates with active promoters and gene transcription. This modification is catalyzed by KMT2 methyltransferases, which require interaction with 4 core subunits, WDR5, RBBP5, ASH2L and DPY30, for catalytic activity. Ash2l is necessary for organismal development and for tissue homeostasis. In mouse embryo fibroblasts (MEFs), Ash2l loss results in gene repression, provoking a senescence phenotype. We now find that upon knockout of Ash2l both H3K4 mono- and tri-methylation (H3K4me1 and me3, respectively) were deregulated. In particular, loss of H3K4me3 at promoters correlated with gene repression, especially at CpG island promoters. Ash2l loss resulted in increased loading of histone H3 and reduced chromatin accessibility at promoters, accompanied by an increase of repressing and a decrease of activating histone marks. Moreover, we observed altered binding of CTCF upon Ash2l loss. Lost and gained binding was noticed at promoter-associated and intergenic sites, respectively. Thus, Ash2l loss and reduction of H3K4me3 correlate with altered chromatin accessibility and transcription factor binding. These findings contribute to a more detailed understanding of mechanistic consequences of H3K4me3 loss and associated repression of gene transcription and thus of the observed cellular consequences.
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Affiliation(s)
- Mirna Barsoum
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Alexander T. Stenzel
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Agnieszka Bochyńska
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Chao-Chung Kuo
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany ,grid.1957.a0000 0001 0728 696XInterdisciplinary Center for Clinical Research (IZKF), Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Alexander Tsompanidis
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Roksaneh Sayadi-Boroujeni
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Philip Bussmann
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Juliane Lüscher-Firzlaff
- grid.1957.a0000 0001 0728 696XInstitute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Ivan G. Costa
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Bernhard Lüscher
- Institute of Biochemistry and Molecular Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
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Feng J, Meng X. Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond. Front Pharmacol 2022; 13:946811. [PMID: 36188615 PMCID: PMC9522521 DOI: 10.3389/fphar.2022.946811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/15/2022] [Indexed: 12/21/2022] Open
Abstract
Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.
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