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Lim YJ, Lee YH. Solo or in Concert: SUMOylation in Pathogenic Fungi. THE PLANT PATHOLOGY JOURNAL 2025; 41:140-152. [PMID: 40211619 PMCID: PMC11986368 DOI: 10.5423/ppj.rw.11.2024.0180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 04/14/2025]
Abstract
SUMOylation plays a pivotal role in DNA replication and repair, transcriptional stability, and stress response. Although SUMOylation is a conserved posttranslational modification (PTM) in eukaryotes, the number, type, and function of SUMOylation-associated components vary among mammals, plants, and fungi. SUMOylation shares overlapping features with ubiquitination, another well-known PTM. However, comparative studies on the interplay between these two PTMs are largely limited to yeast among fungal species. Recently, the role of SUMOylation in pathogenicity and its potential for crosstalk with ubiquitination have gained attention in fungal pathogens. In this review, we summarize recent findings on the distinct components of SUMOylation across organisms and describe its critical functions in fungal pathogens. Furthermore, we propose new research directions for SUMOylation in fungal pathogens, both independently and in coordination with other PTMs. This review aims to illuminate the potential for advancing PTM crosstalk research in fungal systems.
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Affiliation(s)
- You-Jin Lim
- Research Institute of Agriculture and Life Sciences and Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
| | - Yong-Hwan Lee
- Research Institute of Agriculture and Life Sciences and Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
- Interdisciplinary Program in Agricultural Genomics, Center for Fungal Genetic Resources, Plant Immunity Research Center, and Center for Plant Microbiome Research, Seoul National University, Seoul 08826, Korea
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2
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Batra SS, Cabrera A, Spence JP, Goell J, Anand SS, Hilton IB, Song YS. Predicting the effect of CRISPR-Cas9-based epigenome editing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.10.03.560674. [PMID: 37873127 PMCID: PMC10592942 DOI: 10.1101/2023.10.03.560674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~ 0.70 - 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.
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Affiliation(s)
- Sanjit Singh Batra
- Equally contributing authors
- Computer Science Division, University of California, Berkeley, CA 94720
| | - Alan Cabrera
- Equally contributing authors
- Department of Bioengineering, Rice University, TX 77005
| | - Jeffrey P. Spence
- Equally contributing authors
- Department of Genetics, Stanford University, CA 94305
| | - Jacob Goell
- Department of Bioengineering, Rice University, TX 77005
| | - Selvalakshmi S. Anand
- Systems, Synthetic, and Physical Biology Graduate Program, Rice University, TX 77005
| | - Isaac B. Hilton
- Department of Bioengineering, Rice University, TX 77005
- Systems, Synthetic, and Physical Biology Graduate Program, Rice University, TX 77005
| | - Yun S. Song
- Computer Science Division, University of California, Berkeley, CA 94720
- Department of Statistics, University of California, Berkeley, CA 94720
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3
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Verdier E, Gaspar N, Marques Da Costa ME, Marchais A. SETDB1 amplification in osteosarcomas: Insights from its role in healthy tissues and other cancer types. Oncotarget 2025; 16:51-62. [PMID: 39945463 PMCID: PMC11823473 DOI: 10.18632/oncotarget.28688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
Epigenetic modifications, which reversibly regulate gene expression without altering the DNA sequence, are increasingly described in the literature as essential elements in the processes leading to cancer development. SETDB1 regulates histone 3 (H3) K9 di- and trimethylation, promoting heterochromatin formation, and plays a key role in gene silencing. Epigenetic deregulation of SETDB1 expression appears to be involved in different cancers types, particularly in aggressive, relapsing or treatment-resistant subtypes. Despite advances in research, the full range of mechanisms through which this protein acts remains unclear; however, it is evident that SETDB1 has a pivotal role, particularly in the mesenchymal stem cells differentiation, tumor evasion and treatment resistance. Its role in genetically complex sarcomas, such as osteosarcoma, has not been fully explored, although recent Omics analyses suggest its presence and amplification in osteosarcoma. Given its involvement in osteoblastogenesis and adipogenesis, we discuss the potential of SETDB1 as a key target for new therapeutic strategies in osteosarcoma.
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Affiliation(s)
- Elodie Verdier
- UMR 1015 Tumour Immunology and anti-cancer immunotherapy Unit, Gustave Roussy Cancer Campus, Villejuif 94800, France
- Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif 94805, France
| | - Nathalie Gaspar
- UMR 1015 Tumour Immunology and anti-cancer immunotherapy Unit, Gustave Roussy Cancer Campus, Villejuif 94800, France
- Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif 94805, France
| | - Maria Eugenia Marques Da Costa
- UMR 1015 Tumour Immunology and anti-cancer immunotherapy Unit, Gustave Roussy Cancer Campus, Villejuif 94800, France
- Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif 94805, France
| | - Antonin Marchais
- UMR 1015 Tumour Immunology and anti-cancer immunotherapy Unit, Gustave Roussy Cancer Campus, Villejuif 94800, France
- Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif 94805, France
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4
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Pop NS, Dolt KS, Hohenstein P. Understanding developing kidneys and Wilms tumors one cell at a time. Curr Top Dev Biol 2025; 163:129-167. [PMID: 40254343 DOI: 10.1016/bs.ctdb.2024.11.005] [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] [Indexed: 04/22/2025]
Abstract
Single-cell sequencing-based techniques are revolutionizing all fields of biomedical sciences, including normal kidney development and how this is disturbed in the development of Wilms tumor. The many different techniques and the differences between them can obscure which technique is best used to answer which question. In this review we summarize the techniques currently available, discuss which have been used in kidney development or Wilms tumor context, and which techniques can or should be combined to maximize the increase in biological understanding we can get from them.
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Affiliation(s)
- Nine Solee Pop
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Karamjit Singh Dolt
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Peter Hohenstein
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
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5
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Cao Q, Xu W, Chen X, Luo G, Reinach PS, Yan D. PRMT1-Mediated Arginine Methylation Promotes Corneal Epithelial Wound Healing via Epigenetic Regulation of ANXA3. Invest Ophthalmol Vis Sci 2025; 66:22. [PMID: 39786757 PMCID: PMC11725987 DOI: 10.1167/iovs.66.1.22] [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: 07/25/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025] Open
Abstract
Purpose Protein arginine methyltransferase 1 (PRMT1) is an integral constituent of numerous cellular processes. However, its role in corneal epithelial wound healing (CEWH) remains unclear. This study investigates the impact of PRMT1 on cellular mechanisms underlying corneal epithelial repair and its potential to improve wound healing outcomes. Methods The murine CEWH model was established using an Alger brush. Corneal epithelial-specific Prmt1 knockout mice were generated using the Cre-lox system. Quantitative reverse transcription polymerase chain reaction and Western blot analyses determined the expression of candidate genes at mRNA and protein expression levels. Human corneal epithelial cells (HCECs) were transfected with siRNA using Lipofectamine RNAiMAX or infected with lentivirus to precisely alter the expression of PRMT1 or Annexin A3 (ANXA3). EdU and a scratch wound-healing assay evaluated the effects of PRMT1 or ANXA3 on HCEC proliferation and migration, respectively. Rescue experiment and chromatin immunoprecipitation assay validate the correlation between PRMT1 and ANXA3. Results Prmt1 is significantly upregulated during CEWH, accompanied by an elevated global arginine methylation level. Knockdown of PRMT1 in HCECs or in vivo knockout impairs cell proliferation, migration, and the CEWH process. Furthermore, ANXA3 was identified as a critical target of PRMT1, with PRMT1 enhancing ANXA3 expression through histone arginine methylation at its promoter region, establishing a causal correlation between them. Moreover, PRMT1 can modulate the NF-κB and JNK signaling pathways via ANXA3. Conclusions PRMT1 is a critical epigenetic regulator in CEWH, promoting wound healing by upregulating ANXA3 via histone arginine methylation. These findings highlight the potential of targeting PRMT1 to enhance corneal epithelial repair.
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Affiliation(s)
- Qiongjie Cao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wenji Xu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xiaoyan Chen
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Guangying Luo
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Peter S. Reinach
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dongsheng Yan
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
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6
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Lyu Y, Kim SJ, Humphrey ES, Nayak R, Guan Y, Liang Q, Kim KH, Tan Y, Dou J, Sun H, Song X, Nagarajan P, Gerner-Mauro KN, Jin K, Liu V, Hassan RH, Johnson ML, Deliu LP, You Y, Sharma A, Pasolli HA, Lu Y, Zhang J, Mohanty V, Chen K, Yang YJ, Chen T, Ge Y. Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration. Cell 2024; 187:7414-7432.e26. [PMID: 39476839 DOI: 10.1016/j.cell.2024.10.007] [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: 02/05/2024] [Revised: 06/14/2024] [Accepted: 10/04/2024] [Indexed: 12/29/2024]
Abstract
Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors and antiviral-independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase ten-eleven translocation (TET)-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration.
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Affiliation(s)
- Ying Lyu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Soo Jin Kim
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Ericka S Humphrey
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Richa Nayak
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Yinglu Guan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingnan Liang
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Kun Hee Kim
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Yukun Tan
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Jinzhuang Dou
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Huandong Sun
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Xingzhi Song
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | | | - Kamryn N Gerner-Mauro
- Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; Development, Disease Models, and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, USA
| | - Kevin Jin
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Wiess School of Natural Sciences, Rice University, Houston, TX, USA
| | - Virginia Liu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Wiess School of Natural Sciences, Rice University, Houston, TX, USA
| | - Rehman H Hassan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Miranda L Johnson
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lisa P Deliu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun You
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anurag Sharma
- Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA
| | - H Amalia Pasolli
- Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Ken Chen
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Youn Joo Yang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Taiping Chen
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA.
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7
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Rong M, Gao SX, Huang PC, Guo YW, Wen D, Jiang JM, Xu YH, Wei JH. Genome-wide identification of the histone modification gene family in Aquilaria sinensis and functional analysis of several HMs in response to MeJA and NaCl stress. Int J Biol Macromol 2024; 281:135871. [PMID: 39357718 DOI: 10.1016/j.ijbiomac.2024.135871] [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: 07/04/2024] [Revised: 09/19/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024]
Abstract
Histone modifications (HMs) play various roles in growth, development, and resistance to abiotic stress. However, HMs have been systematically identified in a few plants, and identification of HMs in medicinal plants is very rare. Aquilaria sinensis is a typical stress-induced medicinal plant, in which HMs remain unexplored. We conducted a comprehensive study to identify HMs and obtained 123 HMs. To conduct evolutionary analysis, we constructed phylogenetic trees and analyzed gene structures. To conduct functional analysis, we performed promoter, GO, and KEGG analyses and ortholog analyses against AtHMs. Based on the expression profiles of different tissues and different layers of Agar-Wit, some HMs of A. sinensis (AsHMs) were predicted to be involved in the formation of agarwood, and their response to MeJA and NaCl stress was tested by qRT-PCR analysis. By analyzing the enrichment of H3K4me3, H3K27me3, and H4K5ac in the promoter regions of two key sesquiterpene synthase genes, AsTPS13/18, we hypothesized that AsHMs play important roles in the synthesis of agarwood sesquiterpenes. We confirmed this hypothesis by conducting RNAi transgenic interference experiments. This study provided valuable information and important biological theories for studying epigenetic regulation in the formation of agarwood. It also provided a framework for conducting further studies on the biological functions of HMs.
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Affiliation(s)
- Mei Rong
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Shi-Xi Gao
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Peng-Cheng Huang
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Yu-Wei Guo
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Dong Wen
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Jie-Mei Jiang
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China
| | - Yan-Hong Xu
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
| | - Jian-He Wei
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education & National Engineering Laboratory for Breeding of Endangered Medicinal Materials, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; Hainan Provincial Key Laboratory of Resources Conservation and Development of Southern Medicine & Key Laboratory of State Administration of Traditional Chinese Medicine for Agarwood Sustainable Utilization, Hainan Branch of the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Haikou 570311, China.
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8
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Xie C, Tian Q, Qiu H, Wang R, Wang L, Yue Y, Yang X. Methylation Modification in Ornamental Plants: Impact on Floral Aroma and Color. Int J Mol Sci 2024; 25:8267. [PMID: 39125834 PMCID: PMC11311783 DOI: 10.3390/ijms25158267] [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: 06/12/2024] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 08/12/2024] Open
Abstract
Methylation represents a crucial class of modification that orchestrates a spectrum of regulatory roles in plants, impacting ornamental characteristics, growth, development, and responses to abiotic stress. The establishment and maintenance of methylation involve the coordinated actions of multiple regulatory factors. Methyltransferases play a pivotal role by specifically recognizing and methylating targeted sites, which induces alterations in chromatin structure and gene expression, subsequently influencing the release of volatile aromatic substances and the accumulation of pigments in plant petals. In this paper, we review the regulatory mechanisms of methylation modification reactions and their effects on the changes in aromatic substances and pigments in plant petals. We also explore the potential of methylation modifications to unravel the regulatory mechanisms underlying aroma and color in plant petals. This aims to further elucidate the synthesis, metabolism, and regulatory mechanisms of various methylation modifications related to the aroma and color substances in plant petals, thereby providing a theoretical reference for improving the aroma and color of plant petals.
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Affiliation(s)
- Chenchen Xie
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Qingyin Tian
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Hanruo Qiu
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Rui Wang
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Lianggui Wang
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Yuanzheng Yue
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
| | - Xiulian Yang
- Key Laboratory of Landscape Architecture, College of Landscape Architecture, Nanjing Forestry University, Nanjing 210037, China; (C.X.); (Q.T.); (H.Q.); (R.W.); (L.W.)
- Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China
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9
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Liu TA, Stewart TM, Casero RA. The Synergistic Benefit of Combination Strategies Targeting Tumor Cell Polyamine Homeostasis. Int J Mol Sci 2024; 25:8173. [PMID: 39125742 PMCID: PMC11311409 DOI: 10.3390/ijms25158173] [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: 06/05/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Mammalian polyamines, including putrescine, spermidine, and spermine, are positively charged amines that are essential for all living cells including neoplastic cells. An increasing understanding of polyamine metabolism, its molecular functions, and its role in cancer has led to the interest in targeting polyamine metabolism as an anticancer strategy, as the metabolism of polyamines is frequently dysregulated in neoplastic disease. In addition, due to compensatory mechanisms, combination therapies are clinically more promising, as agents can work synergistically to achieve an effect beyond that of each strategy as a single agent. In this article, the nature of polyamines, their association with carcinogenesis, and the potential use of targeting polyamine metabolism in treating and preventing cancer as well as combination therapies are described. The goal is to review the latest strategies for targeting polyamine metabolism, highlighting new avenues for exploiting aberrant polyamine homeostasis for anticancer therapy and the mechanisms behind them.
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Affiliation(s)
- Ting-Ann Liu
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA;
| | - Tracy Murray Stewart
- The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA;
| | - Robert A. Casero
- The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA;
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10
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Lu Z, Xiao X, Zheng Q, Wang X, Xu L. Assessing next-generation sequencing-based computational methods for predicting transcriptional regulators with query gene sets. Brief Bioinform 2024; 25:bbae366. [PMID: 39082650 PMCID: PMC11289684 DOI: 10.1093/bib/bbae366] [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: 03/19/2024] [Revised: 06/21/2024] [Accepted: 07/18/2024] [Indexed: 08/03/2024] Open
Abstract
This article provides an in-depth review of computational methods for predicting transcriptional regulators (TRs) with query gene sets. Identification of TRs is of utmost importance in many biological applications, including but not limited to elucidating biological development mechanisms, identifying key disease genes, and predicting therapeutic targets. Various computational methods based on next-generation sequencing (NGS) data have been developed in the past decade, yet no systematic evaluation of NGS-based methods has been offered. We classified these methods into two categories based on shared characteristics, namely library-based and region-based methods. We further conducted benchmark studies to evaluate the accuracy, sensitivity, coverage, and usability of NGS-based methods with molecular experimental datasets. Results show that BART, ChIP-Atlas, and Lisa have relatively better performance. Besides, we point out the limitations of NGS-based methods and explore potential directions for further improvement.
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Affiliation(s)
- Zeyu Lu
- Department of Statistics and Data Science, Moody School of Graduate and Advanced Studies, Southern Methodist University, 3225 Daniel Ave., P.O. Box 750332, Dallas, TX, United States
| | - Xue Xiao
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, United States
| | - Qiang Zheng
- Division of Data Science, College of Science, University of Texas at Arlington, 501 S. Nedderman Dr., Arlington, TX 76019, United States
| | - Xinlei Wang
- Division of Data Science, College of Science, University of Texas at Arlington, 501 S. Nedderman Dr., Arlington, TX 76019, United States
- Department of Mathematics, University of Texas at Arlington, 411 S. Nedderman Dr., Arlington, TX 76019, United States
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, United States
- Department of Pediatrics, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States
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11
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Mensah IK, Gowher H. Epigenetic Regulation of Mammalian Cardiomyocyte Development. EPIGENOMES 2024; 8:25. [PMID: 39051183 PMCID: PMC11270418 DOI: 10.3390/epigenomes8030025] [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: 05/07/2024] [Revised: 06/07/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
The heart is the first organ formed during mammalian development and functions to distribute nutrients and oxygen to other parts of the developing embryo. Cardiomyocytes are the major cell types of the heart and provide both structural support and contractile function to the heart. The successful differentiation of cardiomyocytes during early development is under tight regulation by physical and molecular factors. We have reviewed current studies on epigenetic factors critical for cardiomyocyte differentiation, including DNA methylation, histone modifications, chromatin remodelers, and noncoding RNAs. This review also provides comprehensive details on structural and morphological changes associated with the differentiation of fetal and postnatal cardiomyocytes and highlights their differences. A holistic understanding of all aspects of cardiomyocyte development is critical for the successful in vitro differentiation of cardiomyocytes for therapeutic purposes.
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Affiliation(s)
| | - Humaira Gowher
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
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12
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Yi HB, Lee S, Seo K, Kim H, Kim M, Lee HS. Cellular and Biophysical Applications of Genetic Code Expansion. Chem Rev 2024; 124:7465-7530. [PMID: 38753805 DOI: 10.1021/acs.chemrev.4c00112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
Despite their diverse functions, proteins are inherently constructed from a limited set of building blocks. These compositional constraints pose significant challenges to protein research and its practical applications. Strategically manipulating the cellular protein synthesis system to incorporate novel building blocks has emerged as a critical approach for overcoming these constraints in protein research and application. In the past two decades, the field of genetic code expansion (GCE) has achieved significant advancements, enabling the integration of numerous novel functionalities into proteins across a variety of organisms. This technological evolution has paved the way for the extensive application of genetic code expansion across multiple domains, including protein imaging, the introduction of probes for protein research, analysis of protein-protein interactions, spatiotemporal control of protein function, exploration of proteome changes induced by external stimuli, and the synthesis of proteins endowed with novel functions. In this comprehensive Review, we aim to provide an overview of cellular and biophysical applications that have employed GCE technology over the past two decades.
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Affiliation(s)
- Han Bin Yi
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Seungeun Lee
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Kyungdeok Seo
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Hyeongjo Kim
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Minah Kim
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Hyun Soo Lee
- Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
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13
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Jia J, Fan H, Wan X, Fang Y, Li Z, Tang Y, Zhang Y, Huang J, Fang D. FUS reads histone H3K36me3 to regulate alternative polyadenylation. Nucleic Acids Res 2024; 52:5549-5571. [PMID: 38499486 PMCID: PMC11162772 DOI: 10.1093/nar/gkae184] [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: 05/17/2023] [Revised: 02/18/2024] [Accepted: 03/04/2024] [Indexed: 03/20/2024] Open
Abstract
Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3 recognition of FUS was mediated by the proline residues in the ZNF domain. After these proline residues were mutated or H3K36me3 was abolished, FUS dissociated from chromatin and bound more to RNA, resulting in an increase in polyadenylation sites far from stop codons genome-wide. A proline mutation corresponding to a mutation in amyotrophic lateral sclerosis contributed to the hyperactivation of mitochondria and hyperdifferentiation in mouse embryonic stem cells. These findings reveal that FUS is an H3K36me3 reader protein that links chromatin-mediated alternative polyadenylation to human disease.
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Affiliation(s)
- Junqi Jia
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Haonan Fan
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Xinyi Wan
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yuan Fang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zhuoning Li
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yin Tang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yanjun Zhang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jun Huang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Dong Fang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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14
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Wang C, Hu B, Yang Y, Wang Y, Qin J, Wen X, Li Y, Li H, Wang Y, Wang J, Liu Y. Structural simulation and selective inhibitor discovery study for histone demethylases KDM4E/6B from a computational perspective. Comput Biol Chem 2024; 110:108072. [PMID: 38636391 DOI: 10.1016/j.compbiolchem.2024.108072] [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: 01/08/2024] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/20/2024]
Abstract
The methylation and demethylation of lysine and arginine side chains are fundamental processes in gene regulation and disease development. Histone lysine methylation, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), plays a vital role in maintaining cellular homeostasis and has been implicated in diseases such as cancer and aging. This study focuses on two members of the lysine demethylase (KDM) family, KDM4E and KDM6B, which are significant in gene regulation and disease pathogenesis. KDM4E demonstrates selectivity for gene regulation, particularly concerning cancer, while KDM6B is implicated in inflammation and cancer. The study utilizes specific inhibitors, DA-24905 and GSK-J1, showcasing their exceptional selectivity for KDM4E and KDM6B, respectively. Employing an array of computational simulations, including sequence alignment, molecular docking, dynamics simulations, and free energy calculations, we conclude that although the binding cavities of KDM4E and KDM6B has high similarity, there are still some different crucial amino acid residues, indicating diverse binding forms between protein and ligands. Various interaction predominates when proteins are bound to different ligands, which also has significant effect on selective inhibition. These findings provide insights into potential therapeutic strategies for diseases by selectively targeting these KDM members.
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Affiliation(s)
- Chenxiao Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Baichun Hu
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Benxi 117004, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yi Yang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Yihan Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Juyue Qin
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Xiaolian Wen
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Yikuan Li
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Hui Li
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Yutong Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Benxi 117004, China
| | - Jian Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Benxi 117004, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yang Liu
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Benxi 117004, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China.
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15
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Missong H, Joshi R, Khullar N, Thareja S, Navik U, Bhatti GK, Bhatti JS. Nutrient-epigenome interactions: Implications for personalized nutrition against aging-associated diseases. J Nutr Biochem 2024; 127:109592. [PMID: 38325612 DOI: 10.1016/j.jnutbio.2024.109592] [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: 10/15/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/09/2024]
Abstract
Aging is a multifaceted process involving genetic and environmental interactions often resulting in epigenetic changes, potentially leading to aging-related diseases. Various strategies, like dietary interventions and calorie restrictions, have been employed to modify these epigenetic landscapes. A burgeoning field of interest focuses on the role of microbiota in human health, emphasizing system biology and computational approaches. These methods help decipher the intricate interplay between diet and gut microbiota, facilitating the creation of personalized nutrition strategies. In this review, we analysed the mechanisms related to nutritional interventions while highlighting the influence of dietary strategies, like calorie restriction and intermittent fasting, on microbial composition and function. We explore how gut microbiota affects the efficacy of interventions using tools like multi-omics data integration, network analysis, and machine learning. These tools enable us to pinpoint critical regulatory elements and generate individualized models for dietary responses. Lastly, we emphasize the need for a deeper comprehension of nutrient-epigenome interactions and the potential of personalized nutrition informed by individual genetic and epigenetic profiles. As knowledge and technology advance, dietary epigenetics stands on the cusp of reshaping our strategy against aging and related diseases.
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Affiliation(s)
- Hemi Missong
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Riya Joshi
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab, India
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India.
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16
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Huang X, Chen Y, Xiao Q, Shang X, Liu Y. Chemical inhibitors targeting histone methylation readers. Pharmacol Ther 2024; 256:108614. [PMID: 38401773 DOI: 10.1016/j.pharmthera.2024.108614] [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: 12/19/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/26/2024]
Abstract
Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.
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Affiliation(s)
- Xiaolei Huang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yichang Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Qin Xiao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Xinci Shang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yanli Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China.
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17
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Burenkova OV, Grigorenko EL. The role of epigenetic mechanisms in the long-term effects of early-life adversity and mother-infant relationship on physiology and behavior of offspring in laboratory rats and mice. Dev Psychobiol 2024; 66:e22479. [PMID: 38470450 PMCID: PMC10959231 DOI: 10.1002/dev.22479] [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: 09/15/2023] [Revised: 01/23/2024] [Accepted: 02/16/2024] [Indexed: 03/13/2024]
Abstract
Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.
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Affiliation(s)
- Olga V. Burenkova
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Department of Integrative Biology, University of Guelph, Guelph, Ontario, Canada
| | - Elena L. Grigorenko
- Department of Psychology, University of Houston, Houston, Texas, USA
- Texas Institute for Measurement, Evaluation, and Statistics, University of Houston, Houston, Texas, USA
- Center for Cognitive Sciences, Sirius University of Science and Technology, Sochi, Russia
- Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Child Study Center, Yale University, New Haven, Connecticut, USA
- Research Administration, Moscow State University for Psychology and Education, Moscow, Russia
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18
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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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19
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Frisbie VS, Hashimoto H, Xie Y, De Luna Vitorino FN, Baeza J, Nguyen T, Yuan Z, Kiselar J, Garcia BA, Debler EW. Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids. Nat Commun 2024; 15:2467. [PMID: 38503750 PMCID: PMC10951340 DOI: 10.1038/s41467-024-46637-6] [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: 08/04/2023] [Accepted: 03/04/2024] [Indexed: 03/21/2024] Open
Abstract
In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (Gx6K) is essential to stabilize the DOT1A enzyme-substrate complex, while substitution of the motif X sequence VYGE by CAKS renders a rigid active-site loop flexible, implying a distinct mechanism of substrate recognition. We further reveal distinct methylation kinetics and substrate preferences of DOT1A (H3K76me0) and DOT1B (DOT1A products H3K76me1/me2) in vitro, determined by a Ser and Ala residue within motif IV, respectively, enabling DOT1A and DOT1B to mediate efficient H3K76 tri-methylation non-processively but cooperatively, and suggesting why kinetoplastids have evolved two DOT1 enzymes.
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Affiliation(s)
- Victoria S Frisbie
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hideharu Hashimoto
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Yixuan Xie
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
- Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Francisca N De Luna Vitorino
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
| | - Josue Baeza
- Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Tam Nguyen
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Zhangerjiao Yuan
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Janna Kiselar
- Case Center for Proteomics and Bioinformatics, Department of Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
| | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA
- Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Erik W Debler
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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20
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Deng X, Liang S, Tang Y, Li Y, Xu R, Luo L, Wang Q, Zhang X, Liu Y. Adverse effects of bisphenol A and its analogues on male fertility: An epigenetic perspective. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 345:123393. [PMID: 38266695 DOI: 10.1016/j.envpol.2024.123393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/11/2023] [Accepted: 01/17/2024] [Indexed: 01/26/2024]
Abstract
In recent years, there has been growing concern about the adverse effects of endocrine disrupting chemicals (EDCs) on male fertility. Epigenetic modification is critical for male germline development, and has been suggested as a potential mechanism for impaired fertility induced by EDCs. Bisphenol A (BPA) has been recognized as a typical EDC. BPA and its analogues, which are still widely used in various consumer products, have garnered increasing attention due to their reproductive toxicity and the potential to induce epigenetic alteration. This literature review provides an overview of studies investigating the adverse effects of bisphenol exposures on epigenetic modifications and male fertility. Existing studies provide evidence that exposure to bisphenols can lead to adverse effects on male fertility, including declined semen quality, altered reproductive hormone levels, and adverse reproductive outcomes. Epigenetic patterns, including DNA methylation, histone modification, and non-coding RNA expression, can be altered by bisphenol exposures. Transgenerational effects, which influence the fertility and epigenetic patterns of unexposed generations, have also been identified. However, the magnitude and direction of certain outcomes varied across different studies. Investigations into the dynamics of histopathological and epigenetic alterations associated with bisphenol exposures during developmental stages can enhance the understanding of the epigenetic effects of bisphenols, the implication of epigenetic alteration on male fertility, and the health of successive generation.
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Affiliation(s)
- Xinyi Deng
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Sihan Liang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yuqian Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute, Guangdong Provincial Fertility Hospital, Guangzhou, China
| | - Yingxin Li
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ruijun Xu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lu Luo
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Qiling Wang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute, Guangdong Provincial Fertility Hospital, Guangzhou, China
| | - Xinzong Zhang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute, Guangdong Provincial Fertility Hospital, Guangzhou, China
| | - Yuewei Liu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
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21
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Jawarkar RD, Zaki MEA, Al-Hussain SA, Al-Mutairi AA, Samad A, Masand V, Humane V, Mali S, Alzahrani AYA, Rashid S, Elossaily GM. Mechanistic QSAR modeling derived virtual screening, drug repurposing, ADMET and in- vitro evaluation to identify anticancer lead as lysine-specific demethylase 5a inhibitor. J Biomol Struct Dyn 2024:1-31. [PMID: 38385447 DOI: 10.1080/07391102.2024.2319104] [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: 08/24/2023] [Accepted: 02/11/2024] [Indexed: 02/23/2024]
Abstract
A lysine-specific demethylase is an enzyme that selectively eliminates methyl groups from lysine residues. KDM5A, also known as JARID1A or RBP2, belongs to the KDM5 Jumonji histone demethylase subfamily. To identify novel molecules that interact with the LSD5A receptor, we created a quantitative structure-activity relationship (QSAR) model. A group of 435 compounds was used in a study of the quantitative relationship between structure and activity to guess the IC50 values for blocking LASD5A. We used a genetic algorithm-multilinear regression-based quantitative structure-activity connection model to forecast the bioactivity (PIC50) of 1615 food and drug administration pharmaceuticals from the zinc database with the goal of repurposing clinically used medications. We used molecular docking, molecular dynamic simulation modelling, and molecular mechanics generalised surface area analysis to investigate the molecule's binding mechanism. A genetic algorithm and multi-linear regression method were used to make six variable-based quantitative structure-activity relationship models that worked well (R2 = 0.8521, Q2LOO = 0.8438, and Q2LMO = 0.8414). ZINC000000538621 was found to be a new hit against LSD5A after a quantitative structure-activity relationship-based virtual screening of 1615 zinc food and drug administration compounds. The docking analysis revealed that the hit molecule 11 in the KDM5A binding pocket adopted a conformation similar to the pdb-6bh1 ligand (docking score: -8.61 kcal/mol). The results from molecular docking and the quantitative structure-activity relationship were complementary and consistent. The most active lead molecule 11, which has shown encouraging results, has good absorption, distribution, metabolism, and excretion (ADME) properties, and its toxicity has been shown to be minimal. In addition, the MTT assay of ZINC000000538621 with MCF-7 cell lines backs up the in silico studies. We used molecular mechanics generalise borne surface area analysis and a 200-ns molecular dynamics simulation to find structural motifs for KDM5A enzyme interactions. Thus, our strategy will likely expand food and drug administration molecule repurposing research to find better anticancer drugs and therapies.
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Affiliation(s)
- Rahul D Jawarkar
- Department of Medicinal Chemistry and Drug discovery, Dr. Rajendra Gode Institute of Pharmacy, Amravati, Maharashtra, India
| | - Magdi E A Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Sami A Al-Hussain
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Aamal A Al-Mutairi
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Abdul Samad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Vijay Masand
- Department of Chemistry, Amravati, Maharashtra, India
| | - Vivek Humane
- Department of Chemistry, Shri R. R. Lahoti Science college, Morshi District: Amravati, Maharashtra, India
| | - Suraj Mali
- School of Pharmacy, D.Y. Patil University (Deemed to be University), Nerul, Navi Mumbai, India
| | | | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Gehan M Elossaily
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
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22
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Long Y, Mao C, Liu S, Tao Y, Xiao D. Epigenetic modifications in obesity-associated diseases. MedComm (Beijing) 2024; 5:e496. [PMID: 38405061 PMCID: PMC10893559 DOI: 10.1002/mco2.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
The global prevalence of obesity has reached epidemic levels, significantly elevating the susceptibility to various cardiometabolic conditions and certain types of cancer. In addition to causing metabolic abnormalities such as insulin resistance (IR), elevated blood glucose and lipids, and ectopic fat deposition, obesity can also damage pancreatic islet cells, endothelial cells, and cardiomyocytes through chronic inflammation, and even promote the development of a microenvironment conducive to cancer initiation. Improper dietary habits and lack of physical exercise are important behavioral factors that increase the risk of obesity, which can affect gene expression through epigenetic modifications. Epigenetic alterations can occur in early stage of obesity, some of which are reversible, while others persist over time and lead to obesity-related complications. Therefore, the dynamic adjustability of epigenetic modifications can be leveraged to reverse the development of obesity-associated diseases through behavioral interventions, drugs, and bariatric surgery. This review provides a comprehensive summary of the impact of epigenetic regulation on the initiation and development of obesity-associated cancers, type 2 diabetes, and cardiovascular diseases, establishing a theoretical basis for prevention, diagnosis, and treatment of these conditions.
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Affiliation(s)
- Yiqian Long
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunanChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, School of Basic MedicineCentral South UniversityChangshaHunanChina
| | - Chao Mao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, School of Basic MedicineCentral South UniversityChangshaHunanChina
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic MedicineCentral South UniversityChangshaChina
| | - Shuang Liu
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunanChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, School of Basic MedicineCentral South UniversityChangshaHunanChina
- Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaHunanChina
| | - Yongguang Tao
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunanChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, School of Basic MedicineCentral South UniversityChangshaHunanChina
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic MedicineCentral South UniversityChangshaChina
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Department of Thoracic SurgerySecond Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Desheng Xiao
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaHunanChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, School of Basic MedicineCentral South UniversityChangshaHunanChina
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23
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Zhang L, Chai R, Tai Z, Miao F, Shi X, Chen Z, Zhu Q. Noval advance of histone modification in inflammatory skin diseases and related treatment methods. Front Immunol 2024; 14:1286776. [PMID: 38235133 PMCID: PMC10792063 DOI: 10.3389/fimmu.2023.1286776] [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: 09/01/2023] [Accepted: 12/08/2023] [Indexed: 01/19/2024] Open
Abstract
Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.
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Affiliation(s)
- Lichen Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Rongrong Chai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Fengze Miao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Xinwei Shi
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, China
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24
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Yagci ZB, Kelkar GR, Johnson TJ, Sen D, Keung AJ. Designing Epigenome Editors: Considerations of Biochemical and Locus Specificities. Methods Mol Biol 2024; 2842:23-55. [PMID: 39012589 DOI: 10.1007/978-1-0716-4051-7_2] [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] [Indexed: 07/17/2024]
Abstract
The advent of locus-specific protein recruitment technologies has enabled a new class of studies in chromatin biology. Epigenome editors (EEs) enable biochemical modifications of chromatin at almost any specific endogenous locus. Their locus-specificity unlocks unique information including the functional roles of distinct modifications at specific genomic loci. Given the growing interest in using these tools for biological and translational studies, there are many specific design considerations depending on the scientific question or clinical need. Here, we present and discuss important design considerations and challenges regarding the biochemical and locus specificities of epigenome editors. These include how to: account for the complex biochemical diversity of chromatin; control for potential interdependency of epigenome editors and their resultant modifications; avoid sequestration effects; quantify the locus specificity of epigenome editors; and improve locus-specificity by considering concentration, affinity, avidity, and sequestration effects.
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Affiliation(s)
- Z Begum Yagci
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA
| | - Gautami R Kelkar
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA
| | - Tyler J Johnson
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA
| | - Dilara Sen
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA
| | - Albert J Keung
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA.
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25
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Zhao Y, Bhatnagar S. Epigenetic Modulations by Microbiome in Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1465:55-69. [PMID: 39586993 DOI: 10.1007/978-3-031-66686-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Recent studies have identified a critical role of the diverse and dynamic microbiome in modulating various aspects of host physiology and intrinsic processes. However, the altered microbiome has also become a hallmark of cancer, which could influence the tumor microenvironment. Aberrations in epigenetic regulation of tumor suppressors, apoptotic genes, and oncogenes can accentuate breast cancer onset and progression. Interestingly, recent studies have established that the microbiota modulates the epigenetic mechanisms at global and gene-specific levels. While the mechanistic basis is unclear, the cross-talk between the microbiome and epigenetics influences breast cancer trajectory. Here, we review different epigenetic mechanisms of mammalian gene expression and summarize the host-associated microbiota distributed across the human body and their influence on cancer and other disease-related genes. Understanding this complex relationship between epigenetics and the microbiome holds promise for new insights into effective therapeutic strategies for breast cancer patients.
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Affiliation(s)
- Yuanji Zhao
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, USA
| | - Sanchita Bhatnagar
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, USA.
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26
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Jankowski K, Jagana V, Bisserier M, Hadri L. Switch-Independent 3A: An Epigenetic Regulator in Cancer with New Implications for Pulmonary Arterial Hypertension. Biomedicines 2023; 12:10. [PMID: 38275371 PMCID: PMC10813728 DOI: 10.3390/biomedicines12010010] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/03/2023] [Accepted: 12/15/2023] [Indexed: 01/27/2024] Open
Abstract
Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA, play a crucial role in the regulation of gene expression and are pivotal in biological processes like apoptosis, cell proliferation, and differentiation. SIN3a serves as a scaffold protein and facilitates interactions with transcriptional epigenetic partners and specific DNA-binding transcription factors to modulate gene expression by adding or removing epigenetic marks. However, the activation or repression of gene expression depends on the factors that interact with SIN3a, as it can recruit both transcriptional activators and repressors. The role of SIN3a has been extensively investigated in the context of cancer, including melanoma, lung, and breast cancer. Our group is interested in defining the roles of SIN3a and its partners in pulmonary vascular disease. Pulmonary arterial hypertension (PAH) is a multifactorial disease often described as a cancer-like disease and characterized by disrupted cellular metabolism, sustained vascular cell proliferation, and resistance to apoptosis. Molecularly, PAH shares many common signaling pathways with cancer cells, offering the opportunity to further consider therapeutic strategies used for cancer. As a result, many signaling pathways observed in cancer were studied in PAH and have encouraged new research studying SIN3a's role in PAH due to its impact on cancer growth. This comparison offers new therapeutic options. In this review, we delineate the SIN3a-associated epigenetic mechanisms in cancer and PAH cells and highlight their impact on cell survival and proliferation. Furthermore, we explore in detail the role of SIN3a in cancer to provide new insights into its emerging role in PAH pathogenesis.
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Affiliation(s)
- Katherine Jankowski
- Center for Translational Medicine and Pharmacology, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Vineeta Jagana
- Department of Cell Biology and Anatomy & Physiology, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY 10595, USA; (V.J.); (M.B.)
| | - Malik Bisserier
- Department of Cell Biology and Anatomy & Physiology, New York Medical College, 15 Dana Road, BSB 131A, Valhalla, NY 10595, USA; (V.J.); (M.B.)
| | - Lahouaria Hadri
- Center for Translational Medicine and Pharmacology, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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27
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Nagasaka M, Inoue Y, Nagao Y, Miyajima C, Morishita D, Aoki H, Aoyama M, Imamura T, Hayashi H. SET8 is a novel negative regulator of TGF-β signaling in a methylation-independent manner. Sci Rep 2023; 13:22877. [PMID: 38129484 PMCID: PMC10739863 DOI: 10.1038/s41598-023-49961-x] [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: 09/25/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Transforming growth factor β (TGF-β) is a multifunctional cytokine that induces a diverse set of cellular processes principally through Smad-dependent transcription. Transcriptional responses induced by Smads are tightly regulated by Smad cofactors and histone modifications; however, the underlying mechanisms have not yet been elucidated in detail. We herein report lysine methyltransferase SET8 as a negative regulator of TGF-β signaling. SET8 physically associates with Smad2/3 and negatively affects transcriptional activation by TGF-β in a catalytic activity-independent manner. The depletion of SET8 results in an increase in TGF-β-induced plasminogen activator inhibitor-1 (PAI-1) and p21 expression and enhances the antiproliferative effects of TGF-β. Mechanistically, SET8 occupies the PAI-1 and p21 promoters, and a treatment with TGF-β triggers the replacement of the suppressive binding of SET8 with p300 on these promoters, possibly to promote gene transcription. Collectively, the present results reveal a novel role for SET8 in the negative regulation of TGF-β signaling.
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Affiliation(s)
- Mai Nagasaka
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Yasumichi Inoue
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
| | - Yuji Nagao
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Chiharu Miyajima
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Daisuke Morishita
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Hiromasa Aoki
- Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Mineyoshi Aoyama
- Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan
| | - Takeshi Imamura
- Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Ehime, 791-0295, Japan
| | - Hidetoshi Hayashi
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
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28
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Kim D, Nam HJ, Baek SH. Post-translational modifications of lysine-specific demethylase 1. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194968. [PMID: 37572976 DOI: 10.1016/j.bbagrm.2023.194968] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/16/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023]
Abstract
Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD+ as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.
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Affiliation(s)
- Dongha Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hye Jin Nam
- Center for Rare Disease Therapeutic Technology, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea.
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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29
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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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30
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Lee S, Menzies L, Hay E, Ochoa E, Docquier F, Rodger F, Deshpande C, Foulds NC, Jacquemont S, Jizi K, Kiep H, Kraus A, Löhner K, Morrison PJ, Popp B, Richardson R, van Haeringen A, Martin E, Toribio A, Li F, Jones WD, Sansbury FH, Maher ER. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders. Hum Mol Genet 2023; 32:3123-3134. [PMID: 37166351 PMCID: PMC10630252 DOI: 10.1093/hmg/ddad079] [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: 02/16/2023] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 05/12/2023] Open
Abstract
Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
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Affiliation(s)
- Sunwoo Lee
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Lara Menzies
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Eleanor Hay
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Eguzkine Ochoa
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - France Docquier
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Fay Rodger
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Charu Deshpande
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary’s Hospital, Manchester, UK
| | - Nicola C Foulds
- Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Sébastien Jacquemont
- CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada
- Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
| | - Khadije Jizi
- CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada
| | - Henriette Kiep
- Department of Neuropediatrics, University Hospital for Children and Adolescents, Leipzig, Germany
| | - Alison Kraus
- Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
| | - Katharina Löhner
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Patrick J Morrison
- Patrick G Johnston Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
| | - Bernt Popp
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Center of Functional Genomics, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Ruth Richardson
- Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Arie van Haeringen
- Department of Clinical Genetics, Leiden University Hospital, Leiden, The Netherlands
| | - Ezequiel Martin
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Ana Toribio
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Fudong Li
- MOE Key Laboratory for Cellular Dynamics, The School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Wendy D Jones
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Francis H Sansbury
- All Wales Medical Genomics Service, NHS Wales Cardiff and Vale University Health Board and Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, UK
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
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31
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Szczepanek J, Tretyn A. MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules 2023; 13:1590. [PMID: 38002272 PMCID: PMC10669115 DOI: 10.3390/biom13111590] [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: 09/21/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, ul. Wilenska 4, 87-100 Torun, Poland
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Torun, Poland;
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32
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Cao MT, Feng Y, Zheng YG. Protein arginine methyltransferase 6 is a novel substrate of protein arginine methyltransferase 1. World J Biol Chem 2023; 14:84-98. [PMID: 37901302 PMCID: PMC10600687 DOI: 10.4331/wjbc.v14.i5.84] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/08/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Post-translational modifications play key roles in various biological processes. Protein arginine methyltransferases (PRMTs) transfer the methyl group to specific arginine residues. Both PRMT1 and PRMT6 have emerges as crucial factors in the development and progression of multiple cancer types. We posit that PRMT1 and PRMT6 might interplay directly or in-directly in multiple ways accounting for shared disease phenotypes. AIM To investigate the mechanism of the interaction between PRMT1 and PRMT6. METHODS Gel electrophoresis autoradiography was performed to test the methyltranferase activity of PRMTs and characterize the kinetics parameters of PRMTs. Liquid chromatography-tandem mass spectrometryanalysis was performed to detect the PRMT6 methylation sites. RESULTS In this study we investigated the interaction between PRMT1 and PRMT6, and PRMT6 was shown to be a novel substrate of PRMT1. We identified specific arginine residues of PRMT6 that are methylated by PRMT1, with R106 being the major methylation site. Combined biochemical and cellular data showed that PRMT1 downregulates the enzymatic activity of PRMT6 in histone H3 methylation. CONCLUSION PRMT6 is methylated by PRMT1 and R106 is a major methylation site induced by PRMT1. PRMT1 methylation suppresses the activity of PRMT6.
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Affiliation(s)
- Meng-Tong Cao
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - You Feng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
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33
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Xu X, Peng Q, Jiang X, Tan S, Yang Y, Yang W, Han Y, Chen Y, Oyang L, Lin J, Xia L, Peng M, Wu N, Tang Y, Li J, Liao Q, Zhou Y. Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential. Exp Mol Med 2023; 55:1357-1370. [PMID: 37394582 PMCID: PMC10394076 DOI: 10.1038/s12276-023-01020-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 03/15/2023] [Accepted: 03/24/2023] [Indexed: 07/04/2023] Open
Abstract
Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.
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Affiliation(s)
- Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- University of South China, Hengyang, 421001, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yiqing Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Wenjuan Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yuyu Chen
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jinyun Li
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
- Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
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Schibler AC, Jevtic P, Pegoraro G, Levy DL, Misteli T. Identification of epigenetic modulators as determinants of nuclear size and shape. eLife 2023; 12:e80653. [PMID: 37219077 PMCID: PMC10259489 DOI: 10.7554/elife.80653] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 05/04/2023] [Indexed: 05/24/2023] Open
Abstract
The shape and size of the human cell nucleus is highly variable among cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters, and eliminating cell cycle effectors, we identified a set of novel determinants of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.
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Affiliation(s)
| | - Predrag Jevtic
- Department of Molecular Biology, University of WyomingLaramieUnited States
| | - Gianluca Pegoraro
- High Throughput Imaging Facility (HiTIF), National Cancer Institute, NIHBethesdaUnited States
| | - Daniel L Levy
- Department of Molecular Biology, University of WyomingLaramieUnited States
| | - Tom Misteli
- National Cancer InstituteBethesdaUnited States
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35
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Saurabh S, Nadendla K, Purohit SS, Sivakumar PM, Cetinel S. Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm. ACS OMEGA 2023; 8:9729-9747. [PMID: 36969402 PMCID: PMC10034788 DOI: 10.1021/acsomega.2c07708] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/17/2023] [Indexed: 06/18/2023]
Abstract
Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure-function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.
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Affiliation(s)
- Suman Saurabh
- Molecular
Sciences Research Hub, Department of Chemistry, Imperial College London, London W12 0BZ, U.K.
| | - Karthik Nadendla
- Center
for Misfolding Diseases, Yusuf Hamied Department of Chemistry, Lensfield
Road, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Shubh Sanket Purohit
- Department
of Clinical Haematology, Sahyadri Superspeciality
Hospital, Pune, Maharashtra 411038, India
| | - Ponnurengam Malliappan Sivakumar
- Institute
of Research and Development, Duy Tan University, Da Nang 550000, Vietnam
- School
of Medicine and Pharmacy, Duy Tan University, Da Nang 550000, Vietnam
- Nanotechnology
Research and Application Center (SUNUM), Sabanci University, Istanbul 34956, Turkey
| | - Sibel Cetinel
- Nanotechnology
Research and Application Center (SUNUM), Sabanci University, Istanbul 34956, Turkey
- Faculty of
Engineering and Natural Sciences, Molecular Biology, Genetics and
Bioengineering Program, Sabanci University, Istanbul 34956, Turkey
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36
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Odroniec A, Olszewska M, Kurpisz M. Epigenetic markers in the embryonal germ cell development and spermatogenesis. Basic Clin Androl 2023; 33:6. [PMID: 36814207 PMCID: PMC9948345 DOI: 10.1186/s12610-022-00179-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 11/25/2022] [Indexed: 02/24/2023] Open
Abstract
Spermatogenesis is the process of generation of male reproductive cells from spermatogonial stem cells in the seminiferous epithelium of the testis. During spermatogenesis, key spermatogenic events such as stem cell self-renewal and commitment to meiosis, meiotic recombination, meiotic sex chromosome inactivation, followed by cellular and chromatin remodeling of elongating spermatids occur, leading to sperm cell production. All the mentioned events are at least partially controlled by the epigenetic modifications of DNA and histones. Additionally, during embryonal development in primordial germ cells, global epigenetic reprogramming of DNA occurs. In this review, we summarized the most important epigenetic modifications in the particular stages of germ cell development, in DNA and histone proteins, starting from primordial germ cells, during embryonal development, and ending with histone-to-protamine transition during spermiogenesis.
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Affiliation(s)
- Amadeusz Odroniec
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60–479 Poznan, Poland
| | - Marta Olszewska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60–479 Poznan, Poland
| | - Maciej Kurpisz
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60–479 Poznan, Poland
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37
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Wang M, Li Q, Liu L. Factors and Methods for the Detection of Gene Expression Regulation. Biomolecules 2023; 13:biom13020304. [PMID: 36830673 PMCID: PMC9953580 DOI: 10.3390/biom13020304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Gene-expression regulation involves multiple processes and a range of regulatory factors. In this review, we describe the key factors that regulate gene expression, including transcription factors (TFs), chromatin accessibility, histone modifications, DNA methylation, and RNA modifications. In addition, we also describe methods that can be used to detect these regulatory factors.
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38
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Wei W, Zhang J, Xu Z, Liu Z, Huang C, Cheng K, Meng L, Matsuda Y, Hao Q, Zhang H, Sun H. Universal Strategy to Develop Fluorogenic Probes for Lysine Deacylase/Demethylase Activity and Application in Discriminating Demethylation States. ACS Sens 2023; 8:28-39. [PMID: 36602906 DOI: 10.1021/acssensors.2c01345] [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: 01/06/2023]
Abstract
Dynamically controlling the post-translational modification of the ε-amino groups of lysine residues is critical for regulating many cellular events. Increasing studies have revealed that many important diseases, including cancer and neurological disorders, are associated with the malfunction of lysine deacylases and demethylases. Developing fluorescent probes that are capable of detecting lysine deacylase and demethylase activity is highly useful for interrogating their roles in epigenetic regulation and diseases. Due to the distinct substrate recognition of these epigenetic eraser enzymes, designing a universal strategy for detecting their activity poses substantial difficulty. Moreover, designing activity-based probes for differentiating their demethylation states is even more challenging and still remains largely unexplored. Herein, we report a universal strategy to construct probes that can detect the enzymatic activity of epigenetic "erasers" through NBD-based long-distance intramolecular reactions. The probes can be easily prepared by installing the O-NBD group at the C-terminal residue of specific peptide substrates by click chemistry. Based on this strategy, detecting the activity of lysine deacetylase, desuccinylase, or demethylase with superior sensitivity and selectivity has been successfully achieved through single-step probe development. Furthermore, the demethylase probe based on this strategy is capable of distinguishing different demethylation states by both absorption and fluorescence lifetime readout. We envision that these newly developed probes will provide powerful tools to facilitate drug discovery in epigenetics in the future.
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Affiliation(s)
- Wenyu Wei
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Jie Zhang
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Zhiqiang Xu
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Zhiyang Liu
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Chen Huang
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Ke Cheng
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Lingkuan Meng
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
| | - Yudai Matsuda
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China
| | - Quan Hao
- Department of Physiology, University of Hong Kong, Pok Fu Lam, Hong Kong999077, China
| | - Huatang Zhang
- School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, Guangdong510006, China
| | - Hongyan Sun
- Department of Chemistry and COSADAF (Centre of Super-Diamond and Advanced Films), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong999077, China.,Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen518057, China
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39
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Bekdash RA. Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection. Int J Mol Sci 2023; 24:ijms24032346. [PMID: 36768667 PMCID: PMC9917111 DOI: 10.3390/ijms24032346] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/18/2023] [Accepted: 01/21/2023] [Indexed: 01/27/2023] Open
Abstract
Methyl donors such as choline, betaine, folic acid, methionine, and vitamins B6 and B12 are critical players in the one-carbon metabolism and have neuroprotective functions. The one-carbon metabolism comprises a series of interconnected chemical pathways that are important for normal cellular functions. Among these pathways are those of the methionine and folate cycles, which contribute to the formation of S-adenosylmethionine (SAM). SAM is the universal methyl donor of methylation reactions such as histone and DNA methylation, two epigenetic mechanisms that regulate gene expression and play roles in human health and disease. Epigenetic mechanisms have been considered a bridge between the effects of environmental factors, such as nutrition, and phenotype. Studies in human and animal models have indicated the importance of the optimal levels of methyl donors on brain health and behavior across the lifespan. Imbalances in the levels of these micronutrients during critical periods of brain development have been linked to epigenetic alterations in the expression of genes that regulate normal brain function. We present studies that support the link between imbalances in the levels of methyl donors, epigenetic alterations, and stress-related disorders. Appropriate levels of these micronutrients should then be monitored at all stages of development for a healthier brain.
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Affiliation(s)
- Rola A Bekdash
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA
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40
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Kim J, Nguyen T, Cifello J, Ahmad R, Zhang Y, Yang Q, Lee JE, Li X, Kai Y, De S, Peng W, Ge K, Weng NP. Lysine methyltransferase Kmt2d regulates naive CD8 + T cell activation-induced survival. Front Immunol 2023; 13:1095140. [PMID: 36741385 PMCID: PMC9892454 DOI: 10.3389/fimmu.2022.1095140] [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: 11/10/2022] [Accepted: 12/30/2022] [Indexed: 01/20/2023] Open
Abstract
Lysine specific methyltransferase 2D (Kmt2d) catalyzes the mono-methylation of histone 3 lysine 4 (H3K4me1) and plays a critical role in regulatory T cell generation via modulating Foxp3 gene expression. Here we report a role of Kmt2d in naïve CD8+ T cell generation and survival. In the absence of Kmt2d, the number of CD8+ T cells, particularly naïve CD8+ T cells (CD62Lhi/CD44lo), in spleen was greatly decreased and in vitro activation-related death significantly increased from Kmt2d fl/flCD4cre+ (KO) compared to Kmt2d fl/flCD4cre- (WT) mice. Furthermore, analyses by ChIPseq, RNAseq, and scRNAseq showed reduced H3K4me1 levels in enhancers and reduced expression of apoptosis-related genes in activated naïve CD8+ T cells in the absence of Kmt2d. Finally, we confirmed the activation-induced death of antigen-specific naïve CD8+ T cells in vivo in Kmt2d KO mice upon challenge with Listeria monocytogenes infection. These findings reveal that Kmt2d regulates activation-induced naïve CD8+ T cell survival via modulating H3K4me1 levels in enhancer regions of apoptosis and immune function-related genes.
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Affiliation(s)
- Jaekwan Kim
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Thomas Nguyen
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Jeffrey Cifello
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Raheel Ahmad
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Yongqing Zhang
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Qian Yang
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Ji-Eun Lee
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Xiang Li
- Department of Physics, George Washington University, Washington DC, WA, United States
| | - Yan Kai
- Department of Physics, George Washington University, Washington DC, WA, United States
| | - Supriyo De
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Weiqun Peng
- Department of Physics, George Washington University, Washington DC, WA, United States
| | - Kai Ge
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Nan-ping Weng
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States,*Correspondence: Nan-ping Weng,
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41
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Yin J, Hong X, Wang J, Li W, Shi Y, Wang D, Liu R. DNA methylation 6 mA and histone methylation involved in multi-/trans-generational reproductive effects in Caenorhabditis elegans induced by Atrazine. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 249:114348. [PMID: 36508798 DOI: 10.1016/j.ecoenv.2022.114348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
Atrazine (ATR), a widely used triazine herbicide, is an environmental endocrine disruptor that can cause health problems. However, whether there are multi/trans-generational reproductive impacts of ATR have not been studied. Therefore, in this study, Caenorhabditis elegans was used as a preferable model organism to identify the multi/trans-generational reproductive toxicity of ATR. Only parental C.elegans (P0) were exposed to different concentrations (0.0004-40 mg/L) for 48 h and the subsequent offspring (F1-F5) were grown under ATR-free conditions and ATR conditions.The results showed that ATR exposure during P0 decreased fecundity, including a reduction in fertilized eggs, oocytes, and ovulation rate, delayed gonadal development, and decreased the relative area of gonad arm and germ cell number. Furthermore, continuous ATR exposure (P0-F5) causes a significant increase in reproductive toxicity in subsequent generations, although no significant toxicity occurred in the P0 generation after exposure to environmental-related concentrations, suggesting that ATR exposure might have cumulative effects. Likewise, parental exposure to ATR caused transgenerational toxicity impairments. Interestingly, only reproductive toxicity, not development toxicity, was transmitted to several generations (F1-F4), and the F2 generation showed the most notable changes. QRT-PCR results showed that genes expression related to DNA methylation 6 mA (damt-1, nmad-1) and histone H3 methylation (mes-4, met-2, set-25, set-2, and utx-1) can also be passed on to offspring. The function of H3K4 and H3K9 methylation were explored by using loss-of-function mutants for set-2, set-25, and met-2. Transmissible reproductive toxicity was absent in met-2(n4256), set-2(ok952), and set-25(n5021) mutants, which suggests that the histone methyltransferases H3K4 and H3K9 activity are indispensable for the transgenerational effect of ATR. Finally, the downstream genes of DNA methylation and histone H3 methylation were determined. ATR upregulated the expression of ZC317.7, hsp-6, and hsp-60. Mitochondrial stress in parental generation dependent transcription 6 mA modifiers may establish these epigenetic marks in progeny.
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Affiliation(s)
- Jiechen Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Xiang Hong
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Jia Wang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Weixi Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Yingchi Shi
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Dayong Wang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
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Tanaka A, Watanabe S. How to improve the clinical outcome of round spermatid injection (ROSI) into the oocyte: Correction of epigenetic abnormalities. Reprod Med Biol 2023; 22:e12503. [PMID: 36789269 PMCID: PMC9909386 DOI: 10.1002/rmb2.12503] [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: 09/09/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 02/11/2023] Open
Abstract
Background First successful human round spermatid injection (ROSI) was conducted by Tesarik et al. in 1996 for the sole treatment of nonobstructive azoospermic men whose most advanced spermatogenic cells were elongating round spermatids. Nine offsprings from ROSI were reported between 1996 and 2000. No successful deliveries were reported for 15 years after that. Tanaka et al. reported 90 babies born after ROSI and their follow-up studies in 2015 and 2018 showed no significant differences in comparison with those born after natural conception in terms of physical and cognitive abilities. However, clinical outcomes remain low. Method Clinical and laboratory data of successful cases in the precursor ROSI groups and those of Tanaka et al. were reviewed. Results Differences were found between the two groups in terms of identification of characteristics of round spermatid and oocyte activation. Additionally, epigenetic abnormalities were identified as underlying causes for poor ROSI results, besides correct identification of round spermatid and adequate oocyte activation. Correction of epigenetic errors could lead to optimal embryonic development. Conclusion Correction of epigenetic abnormalities has a probability to improve the clinical outcome of ROSI.
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Affiliation(s)
- Atsushi Tanaka
- Department of Obstetrics and GynecologySaint Mother ClinicKitakyushuJapan
- Department of Obstetrics and GynecologyJuntendo University School of MedicineBunkyo‐kuJapan
| | - Seiji Watanabe
- Department of Anatomical ScienceHirosaki University Graduate School of MedicineAomoriJapan
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Nunez-Vazquez R, Desvoyes B, Gutierrez C. Histone variants and modifications during abiotic stress response. FRONTIERS IN PLANT SCIENCE 2022; 13:984702. [PMID: 36589114 PMCID: PMC9797984 DOI: 10.3389/fpls.2022.984702] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 09/28/2022] [Indexed: 06/17/2023]
Abstract
Plants have developed multiple mechanisms as an adaptive response to abiotic stresses, such as salinity, drought, heat, cold, and oxidative stress. Understanding these regulatory networks is critical for coping with the negative impact of abiotic stress on crop productivity worldwide and, eventually, for the rational design of strategies to improve plant performance. Plant alterations upon stress are driven by changes in transcriptional regulation, which rely on locus-specific changes in chromatin accessibility. This process encompasses post-translational modifications of histone proteins that alter the DNA-histones binding, the exchange of canonical histones by variants that modify chromatin conformation, and DNA methylation, which has an implication in the silencing and activation of hypervariable genes. Here, we review the current understanding of the role of the major epigenetic modifications during the abiotic stress response and discuss the intricate relationship among them.
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Affiliation(s)
| | - Bénédicte Desvoyes
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Programa de Dinámica y Función del Genoma, Madrid, Spain
| | - Crisanto Gutierrez
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Programa de Dinámica y Función del Genoma, Madrid, Spain
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Nawaz K, Cziesielski MJ, Mariappan KG, Cui G, Aranda M. Histone modifications and DNA methylation act cooperatively in regulating symbiosis genes in the sea anemone Aiptasia. BMC Biol 2022; 20:265. [DOI: 10.1186/s12915-022-01469-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022] Open
Abstract
Abstract
Background
The symbiotic relationship between cnidarians and dinoflagellates is one of the most widespread endosymbiosis in our oceans and provides the ecological basis of coral reef ecosystems. Although many studies have been undertaken to unravel the molecular mechanisms underlying these symbioses, we still know little about the epigenetic mechanisms that control the transcriptional responses to symbiosis.
Results
Here, we used the model organism Exaiptasia diaphana to study the genome-wide patterns and putative functions of the histone modifications H3K27ac, H3K4me3, H3K9ac, H3K36me3, and H3K27me3 in symbiosis. While we find that their functions are generally conserved, we observed that colocalization of more than one modification and or DNA methylation correlated with significantly higher gene expression, suggesting a cooperative action of histone modifications and DNA methylation in promoting gene expression. Analysis of symbiosis genes revealed that activating histone modifications predominantly associated with symbiosis-induced genes involved in glucose metabolism, nitrogen transport, amino acid biosynthesis, and organism growth while symbiosis-suppressed genes were involved in catabolic processes.
Conclusions
Our results provide new insights into the mechanisms of prominent histone modifications and their interaction with DNA methylation in regulating symbiosis in cnidarians.
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Singh G, Bloskie T, Storey KB. Tissue-specific response of the RB-E2F1 complex during mammalian hibernation. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2022; 337:1002-1009. [PMID: 35945704 DOI: 10.1002/jez.2648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/14/2022] [Accepted: 07/25/2022] [Indexed: 06/15/2023]
Abstract
Metabolic rate depression during prolonged bouts of torpor is characteristic of mammalian hibernation, reducing energy expenditures over the winter. Cell cycle arrest is observed in quiescent cells during dormancy, partly due to the retinoblastoma (Rb) protein at G1 /S, given cell division and proliferation are metabolic-costly processes. Rb binds to E2F transcription factors and recruits corepressors (e.g., SUV39H1) to E2F target genes, blocking their transcription and cell cycle passage. Phosphorylation by cyclin-CDK complexes at S780 or S795 abolishes Rb-mediated repression, allowing transition into S phase. The present study compares Rb-E2F1 responses between euthermic and torpid states in five organs (brain, heart, kidney, liver, skeletal muscle) of 13-lined ground squirrels (Ictidomys tridecemlineatus). Immunoblotting assessed the expression of Rb, pRb (S780, S795), E2F1, and SUV39H1. Our findings demonstrate multi-tissue upregulation of Rb and SUV39H1 during torpor, with tissue-specific changes to E2F1 and pRb (S780), suggesting Rb-E2F1 contributes to cell cycle control in hibernation.
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Affiliation(s)
- Gurjit Singh
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Tighe Bloskie
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Kenneth B Storey
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
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Zhao P, Malik S. The phosphorylation to acetylation/methylation cascade in transcriptional regulation: how kinases regulate transcriptional activities of DNA/histone-modifying enzymes. Cell Biosci 2022; 12:83. [PMID: 35659740 PMCID: PMC9164400 DOI: 10.1186/s13578-022-00821-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/27/2022] [Indexed: 11/30/2022] Open
Abstract
Transcription factors directly regulate gene expression by recognizing and binding to specific DNA sequences, involving the dynamic alterations of chromatin structure and the formation of a complex with different kinds of cofactors, like DNA/histone modifying-enzymes, chromatin remodeling factors, and cell cycle factors. Despite the significance of transcription factors, it remains unclear to determine how these cofactors are regulated to cooperate with transcription factors, especially DNA/histone modifying-enzymes. It has been known that DNA/histone modifying-enzymes are regulated by post-translational modifications. And the most common and important modification is phosphorylation. Even though various DNA/histone modifying-enzymes have been classified and partly explained how phosphorylated sites of these enzymes function characteristically in recent studies. It still needs to find out the relationship between phosphorylation of these enzymes and the diseases-associated transcriptional regulation. Here this review describes how phosphorylation affects the transcription activity of these enzymes and other functions, including protein stability, subcellular localization, binding to chromatin, and interaction with other proteins.
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Nagaraju GP, Dariya B, Kasa P, Peela S, El-Rayes BF. Epigenetics in hepatocellular carcinoma. Semin Cancer Biol 2022; 86:622-632. [PMID: 34324953 DOI: 10.1016/j.semcancer.2021.07.017] [Citation(s) in RCA: 156] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/17/2021] [Accepted: 07/25/2021] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has a high fatality rate. Genetic and epigenetic aberrations are commonly observed in HCC. The epigenetic processes include chromatin remodelling, histone alterations, DNA methylation, and noncoding RNA (ncRNA) expression and are connected with the progression and metastasis of HCC. Due to their potential reversibility, these epigenetic alterations are widely targeted for the development of biomarkers. In-depth understanding of the epigenetics of HCC is critical for developing rational clinical strategies that can provide a meaningful improvement in overall survival and prediction of therapeutic outcomes. In this article, we have summarised the epigenetic modifications involved in HCC progression and highlighted the potential biomarkers for diagnosis and drug development.
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Affiliation(s)
- Ganji Purnachandra Nagaraju
- Department of Hematology & Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Begum Dariya
- Department of Biosciences and Biotechnology, Banasthali University, Banasthali, 304022, Rajasthan, India
| | - Prameswari Kasa
- Dr. L.V. Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad 500004, India
| | - Sujatha Peela
- Department of Biotechnology, Dr. B.R. Ambedkar University, Srikakulam, 532410 AP, India
| | - Bassel F El-Rayes
- Department of Hematology & Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
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Zhu Z, Liu Y, Qi J, Sui Z. Identification of epigenetic histone modifications and analysis of histone lysine methyltransferases in Alexandrium pacificum. HARMFUL ALGAE 2022; 119:102323. [PMID: 36344193 DOI: 10.1016/j.hal.2022.102323] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 09/17/2022] [Accepted: 09/21/2022] [Indexed: 06/16/2023]
Abstract
Alexandrium pacificum is a toxic dinoflagellate that can cause harmful algal blooms (HABs). The molecular mechanisms of HABs are still poorly understood, especially at the epigenetics level. Organism growth and metabolic processes are affected by histone modifications, an important mode of epigenetic regulation. In this study, various types of modifications, including methylation, acetylation, ubiquitination, and phosphorylation in A. pacificum cells were identified by using pan-antibodies, mass spectrometry, and an H3 modification multiplex assay kit. The modification abundance of H3K4me2 and H3K27me3 of A. pacificum varied under different growth conditions detected by Western blots. A class of SET domain genes (SDGs) encoding histone lysine methyltransferase was analyzed. A total of 179 SDG members were identified in A. pacificum, of which 53 sequences encoding complete proteins were classified into three categories by phylogenetic analysis, conserved domains and motifs analysis. Expression analysis and real-time polymerase chain reaction validation showed that the expressions of some SDGs were significantly influenced by light, nitrogen, phosphorus and manganese supplements. The results revealed that histone lysine methylation played an important role in responding to HABs inducing conditions. This study provided useful information for the further exploration of the role and regulatory mechanism of SDGs in the rapid growth of A. pacificum.
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Affiliation(s)
- Zhimei Zhu
- Key Laboratory of Marine Genetics and Breeding of Ministry of Education of China, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Yuan Liu
- Key Laboratory of Marine Genetics and Breeding of Ministry of Education of China, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China; College of Agronomy, Qingdao Agricultural University, Qingdao 266109, China
| | - Juan Qi
- Key Laboratory of Marine Genetics and Breeding of Ministry of Education of China, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Zhenghong Sui
- Key Laboratory of Marine Genetics and Breeding of Ministry of Education of China, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
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Hou C, Ye Z, Yang S, Jiang Z, Wang J, Wang E. Lysine demethylase 1B (Kdm1b) enhances somatic reprogramming through inducing pluripotent gene expression and promoting cell proliferation. Exp Cell Res 2022; 420:113339. [PMID: 36075448 DOI: 10.1016/j.yexcr.2022.113339] [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: 02/22/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022]
Abstract
Lysine demethylase 1B (Kdm1b) is known as an epigenetic modifier with demethylase activity against H3K4 and H3K9 histones and plays an important role in tumor progression and tumor stem cell enrichment. In this study, we attempted to elucidate the role of Kdm1b in somatic cell reprogramming. We found that exogenous expression of Kdm1b in human dermal fibroblasts (HDFs) can influence the epigenetic modifications of histones. Subsequent analysis further suggests that the overexpression of Kdm1b can promote cell proliferation, reprogram metabolism and inhibit cell apoptosis. In addition, a series of multipotent factors including Sox2 and Nanog, and several epigenetic factors that may reduce epigenetic barriers were upregulated to varying degrees. More importantly, HDFs transfected with the combination of Oct4 (POU5F1), Sox2, Klf4 and c-Myc and Kdm1b (OSKMK) achieved higher reprogramming efficiency. Therefore, we suggest that Kdm1b is an important epigenetic factor associated with pluripotency.
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Affiliation(s)
- Cuicui Hou
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China; College of Chemistry, Jilin University, Changchun, Jilin, 130021, PR China
| | - Zhikai Ye
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China
| | - Songqin Yang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China
| | - Zhenlong Jiang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China.
| | - Jin Wang
- Department of Chemistry, Physics and Applied Mathematics, State University of New York at Stony Brook, Stony Brook, NY, 11794-3400, United States.
| | - Erkang Wang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, PR China; College of Chemistry, Jilin University, Changchun, Jilin, 130021, PR China.
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Giacoman-Lozano M, Meléndez-Ramírez C, Martinez-Ledesma E, Cuevas-Diaz Duran R, Velasco I. Epigenetics of neural differentiation: Spotlight on enhancers. Front Cell Dev Biol 2022; 10:1001701. [PMID: 36313573 PMCID: PMC9606577 DOI: 10.3389/fcell.2022.1001701] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 10/03/2022] [Indexed: 11/28/2022] Open
Abstract
Neural induction, both in vivo and in vitro, includes cellular and molecular changes that result in phenotypic specialization related to specific transcriptional patterns. These changes are achieved through the implementation of complex gene regulatory networks. Furthermore, these regulatory networks are influenced by epigenetic mechanisms that drive cell heterogeneity and cell-type specificity, in a controlled and complex manner. Epigenetic marks, such as DNA methylation and histone residue modifications, are highly dynamic and stage-specific during neurogenesis. Genome-wide assessment of these modifications has allowed the identification of distinct non-coding regulatory regions involved in neural cell differentiation, maturation, and plasticity. Enhancers are short DNA regulatory regions that bind transcription factors (TFs) and interact with gene promoters to increase transcriptional activity. They are of special interest in neuroscience because they are enriched in neurons and underlie the cell-type-specificity and dynamic gene expression profiles. Classification of the full epigenomic landscape of neural subtypes is important to better understand gene regulation in brain health and during diseases. Advances in novel next-generation high-throughput sequencing technologies, genome editing, Genome-wide association studies (GWAS), stem cell differentiation, and brain organoids are allowing researchers to study brain development and neurodegenerative diseases with an unprecedented resolution. Herein, we describe important epigenetic mechanisms related to neurogenesis in mammals. We focus on the potential roles of neural enhancers in neurogenesis, cell-fate commitment, and neuronal plasticity. We review recent findings on epigenetic regulatory mechanisms involved in neurogenesis and discuss how sequence variations within enhancers may be associated with genetic risk for neurological and psychiatric disorders.
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Affiliation(s)
- Mayela Giacoman-Lozano
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, NL, Mexico
| | - César Meléndez-Ramírez
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Mexico City, Mexico
| | - Emmanuel Martinez-Ledesma
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, NL, Mexico
- Tecnologico de Monterrey, The Institute for Obesity Research, Monterrey, NL, Mexico
| | - Raquel Cuevas-Diaz Duran
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, NL, Mexico
- *Correspondence: Raquel Cuevas-Diaz Duran, ; Iván Velasco,
| | - Iván Velasco
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Mexico City, Mexico
- *Correspondence: Raquel Cuevas-Diaz Duran, ; Iván Velasco,
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