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Cofre J. The first embryo, the origin of cancer and animal phylogeny. V. Cancer stem cells as the unifying biomechanical principle between embryology and oncology. MECHANOBIOLOGY IN MEDICINE 2025; 3:100110. [PMID: 40396136 PMCID: PMC12082149 DOI: 10.1016/j.mbm.2024.100110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/14/2024] [Accepted: 11/27/2024] [Indexed: 05/22/2025]
Abstract
The role of embryology in metazoan evolution is rooted deeply in the history of science. Viewing Neoplasia as an evolutionary engine provides a scientific basis for reexamining the disease cancer. Once the embryo is understood as a benign tumor with a pivotal role in the evolution of all animal forms, there will be an immediate paradigm shift in the search for cancer cure, potentially revealing insights that may be buried within the great developmental transitions of metazoans. This article discusses one of the unifying principles between embryology and oncology, namely cancer stem cells. Some considerations are also provided on the central role of physics and biomechanics in the assembly of the first embryo, which can be regarded as a differentiated benign tumor. Mechanical impregnation of the nucleus of a stem cell, culminating in a totipotent/multipotent cell, was a major event safeguarding the success of embryogenesis throughout evolution. Germ cells in the earliest ctenophore embryos underwent delayed differentiation, subsequent to the mechanical assembly of the embryo. Finally, a discussion is presented on the concept that cancer and embryogenesis (cancer and healthy stem cells) are two sides of the same coin, that is, of the same process. The only difference is that cancer stem cells reveal themselves in inappropriate contexts. Neoplasia is a free force, whereas cancer is a force contained by animal organization.
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Affiliation(s)
- Jaime Cofre
- Laboratório de Embriologia Molecular e Câncer, Federal University of Santa Catarina, Sala 313b, Florianópolis, SC, 88040-900, Brazil
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2
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Toolan KP, McGrath BT, Brinkmeier ML, Camper SA, Bielas SL. Ash1l loss-of-function results in structural birth defects and altered cortical development. Brain 2025; 148:55-68. [PMID: 38943682 PMCID: PMC11706301 DOI: 10.1093/brain/awae218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/16/2024] [Accepted: 06/09/2024] [Indexed: 07/01/2024] Open
Abstract
The histone methyltransferase ASH1L plays a crucial role in regulating gene expression across various organ systems during development, yet its role in brain development remains largely unexplored. Over 130 individuals with autism harbour heterozygous loss-of-function ASH1L variants, and population studies confirm it as a high-risk autism gene. Previous studies on Ash1l deficient mice have reported autistic-like behaviours and provided insights into the underlying neuropathophysiology. In this study, we used mice with a cre-inducible deletion of Ash1l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Our investigation evaluated the impact of Ash1l loss-of-function on survival and craniofacial skeletal development. Using a tamoxifen-inducible cre strain, we targeted Ash1l knockout early in cortical development [Emx1-Cre-ERT2; embryonic Day (e) 10.5]. Immunohistochemistry was utilized to assess cortical lamination, while EdU incorporation aided in birthdating cortical neurons. Additionally, single-cell RNA sequencing was employed to compare cortical cell populations and identify genes with differential expression. At e18.5, the proportion of homozygous Ash1l germline knockout embryos appeared normal; however, no live Ash1l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: n = 41, P = 0.00095). Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017). In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate. Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2 (e13.5 injection: n = 4/genotype, P = 0.0126). Single cell RNA sequencing revealed significant differences in gene expression between control and mutant upper layer neurons, leading to distinct clustering. Pseudotime analysis indicated that the mutant cluster followed an altered cell differentiation trajectory. This study underscores the essential role of Ash1l in postnatal survival and normal craniofacial development. In the cortex, ASH1L exerts broad effects on gene expression and is indispensable for determining the fate of upper layer cortical neurons. These findings provide valuable insights into the potential mechanisms of ASH1L neuropathology, shedding light on its significance in neurodevelopmental disorders like autism.
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Affiliation(s)
- Kevin P Toolan
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI48109, USA
| | - Brian T McGrath
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Michelle L Brinkmeier
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI48109, USA
| | - Sally A Camper
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI48109, USA
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Stephanie L Bielas
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI48109, USA
- Cell and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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3
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Peeters JGC, Silveria S, Ozdemir M, Ramachandran S, DuPage M. Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation. Cell Rep 2024; 43:114724. [PMID: 39264807 PMCID: PMC12052300 DOI: 10.1016/j.celrep.2024.114724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/17/2024] [Accepted: 08/21/2024] [Indexed: 09/14/2024] Open
Abstract
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
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Affiliation(s)
- Janneke G C Peeters
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Stephanie Silveria
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Merve Ozdemir
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Srinivas Ramachandran
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Michel DuPage
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
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Peeters JGC, Silveria S, Ozdemir M, Ramachandran S, DuPage M. Increased EZH2 function in regulatory T cells promotes their capacity to suppress autoimmunity by driving effector differentiation prior to activation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.05.588284. [PMID: 38645261 PMCID: PMC11030251 DOI: 10.1101/2024.04.05.588284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here we assessed whether increased EZH2 activity in Treg cells would improve Treg cell function. Using an Ezh2 gain-of-function mutation, Ezh2 Y641F , we found that Treg cells expressing Ezh2 Y641F displayed an increased effector Treg phenotype and were poised for improved homing to organ tissues. Expression of Ezh2 Y641F in Treg cells led to more rapid remission from autoimmunity. H3K27me3 profiling and transcriptomic analysis revealed a redistribution of H3K27me3, which prompted a gene expression profile in naïve Ezh2 Y641F Treg cells that recapitulated aspects of CD28-activated Ezh2 WT Treg cells. Altogether, increased EZH2 activity promotes the differentiation of effector Treg cells that can better suppress autoimmunity. Highlights EZH2 function promotes effector differentiation of Treg cells.EZH2 function promotes Treg cell migration to organ tissues.EZH2 function in Treg cells improves remission from autoimmunity.EZH2 function poises naïve Treg cells to adopt a CD28-activated phenotype.
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Shi T, Bai Y, Wu X, Wang Y, Iqbal S, Tan W, Ni Z, Gao Z. PmAGAMOUS recruits polycomb protein PmLHP1 to regulate single-pistil morphogenesis in Japanese apricot. PLANT PHYSIOLOGY 2023; 193:466-482. [PMID: 37204822 DOI: 10.1093/plphys/kiad292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 05/20/2023]
Abstract
Japanese apricot (Prunus mume Sieb. et Zucc.) is a traditional fruit tree with a long history. Multiple pistils (MP) lead to the formation of multiple fruits, decreasing fruit quality and yield. In this study, the morphology of flowers was observed at 4 stages of pistil development: undifferentiated stage (S1), predifferentiation stage (S2), differentiation stage (S3), and late differentiation stage (S4). In S2 and S3, the expression of PmWUSCHEL (PmWUS) in the MP cultivar was significantly higher than that in the single-pistil (SP) cultivar, and the gene expression of its inhibitor, PmAGAMOUS (PmAG), also showed the same trend, indicating that other regulators participate in the regulation of PmWUS during this period. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) showed that PmAG could bind to the promoter and the locus of PmWUS, and H3K27me3 repressive marks were also detected at these sites. The SP cultivar exhibited an elevated level of DNA methylation in the promoter region of PmWUS, which partially overlapped with the region of histone methylation. This suggests that the regulation of PmWUS involves both transcription factors and epigenetic modifications. Also, the gene expression of Japanese apricot LIKE HETEROCHROMATIN PROTEIN (PmLHP1), an epigenetic regulator, in MP was significantly lower than that in SP in S2 to 3, contrary to the trend in expression of PmWUS. Our results showed that PmAG recruited sufficient PmLHP1 to maintain the level of H3K27me3 on PmWUS during the S2 of pistil development. This recruitment of PmLHP1 by PmAG inhibits the expression of PmWUS at the precise time, leading to the formation of 1 normal pistil primordium.
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Affiliation(s)
- Ting Shi
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Yang Bai
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Xinxin Wu
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
- College of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China
| | - Yike Wang
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Shahid Iqbal
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
- Horticultural Science Department, North Florida Research and Education Center, University of Florida/IFAS, Quincy, FL 32351, USA
| | - Wei Tan
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhaojun Ni
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhihong Gao
- College of Horticulture, Nanjing Agricultural University, Nanjing 210095, China
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Fal K, Berr A, Le Masson M, Faigenboim A, Pano E, Ishkhneli N, Moyal NL, Villette C, Tomkova D, Chabouté ME, Williams LE, Carles CC. Lysine 27 of histone H3.3 is a fine modulator of developmental gene expression and stands as an epigenetic checkpoint for lignin biosynthesis in Arabidopsis. THE NEW PHYTOLOGIST 2023; 238:1085-1100. [PMID: 36779574 DOI: 10.1111/nph.18666] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 06/18/2023]
Abstract
Chromatin is a dynamic platform within which gene expression is controlled by epigenetic modifications, notably targeting amino acid residues of histone H3. Among them is lysine 27 of H3 (H3K27), the trimethylation of which by the Polycomb Repressive Complex 2 (PRC2) is instrumental in regulating spatiotemporal patterns of key developmental genes. H3K27 is also subjected to acetylation and is found at sites of active transcription. Most information on the function of histone residues and their associated modifications in plants was obtained from studies of loss-of-function mutants for the complexes that modify them. To decrypt the genuine function of H3K27, we expressed a non-modifiable variant of H3 at residue K27 (H3.3K27A ) in Arabidopsis, and developed a multi-scale approach combining in-depth phenotypical and cytological analyses, with transcriptomics and metabolomics. We uncovered that the H3.3K27A variant causes severe developmental defects, part of them are reminiscent of PRC2 mutants, part of them are new. They include early flowering, increased callus formation and short stems with thicker xylem cell layer. This latest phenotype correlates with mis-regulation of phenylpropanoid biosynthesis. Overall, our results reveal novel roles of H3K27 in plant cell fates and metabolic pathways, and highlight an epigenetic control point for elongation and lignin composition of the stem.
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Affiliation(s)
- Kateryna Fal
- Plant and Cell Physiology Lab, IRIG-DBSCI-LPCV, CEA, Grenoble Alpes University - CNRS - INRAE - CEA, 17 rue des Martyrs, bât. C2, 38054, Grenoble Cedex 9, France
| | - Alexandre Berr
- Institut de Biologie Moléculaire des Plantes du CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084, Strasbourg Cedex, France
| | - Marie Le Masson
- Plant and Cell Physiology Lab, IRIG-DBSCI-LPCV, CEA, Grenoble Alpes University - CNRS - INRAE - CEA, 17 rue des Martyrs, bât. C2, 38054, Grenoble Cedex 9, France
| | - Adi Faigenboim
- Institute of Plant Sciences, ARO Volcani Center, PO Box 15159, Rishon LeZion, 7528809, Israel
| | - Emeline Pano
- Plant and Cell Physiology Lab, IRIG-DBSCI-LPCV, CEA, Grenoble Alpes University - CNRS - INRAE - CEA, 17 rue des Martyrs, bât. C2, 38054, Grenoble Cedex 9, France
| | - Nickolay Ishkhneli
- Robert H. Smith Institute of Plant Sciences & Genetics in Agriculture - Hebrew University of Jerusalem, Rehovot, 76100, Israel
| | - Netta-Lee Moyal
- Robert H. Smith Institute of Plant Sciences & Genetics in Agriculture - Hebrew University of Jerusalem, Rehovot, 76100, Israel
| | - Claire Villette
- Institut de Biologie Moléculaire des Plantes du CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084, Strasbourg Cedex, France
| | - Denisa Tomkova
- Institut de Biologie Moléculaire des Plantes du CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084, Strasbourg Cedex, France
| | - Marie-Edith Chabouté
- Institut de Biologie Moléculaire des Plantes du CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084, Strasbourg Cedex, France
| | - Leor Eshed Williams
- Robert H. Smith Institute of Plant Sciences & Genetics in Agriculture - Hebrew University of Jerusalem, Rehovot, 76100, Israel
| | - Cristel C Carles
- Plant and Cell Physiology Lab, IRIG-DBSCI-LPCV, CEA, Grenoble Alpes University - CNRS - INRAE - CEA, 17 rue des Martyrs, bât. C2, 38054, Grenoble Cedex 9, France
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7
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Huang L, Li F, Ye L, Yu F, Wang C. Epigenetic regulation of embryonic ectoderm development in stem cell differentiation and transformation during ontogenesis. Cell Prolif 2023; 56:e13413. [PMID: 36727213 PMCID: PMC10068960 DOI: 10.1111/cpr.13413] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023] Open
Abstract
Dynamic chromatin accessibility regulates stem cell fate determination and tissue homeostasis via controlling gene expression. As a histone-modifying enzyme that predominantly mediates methylation of lysine 27 in histone H3 (H3K27me1/2/3), Polycomb repressive complex 2 (PRC2) plays the canonical role in targeting developmental regulators during stem cell differentiation and transformation. Embryonic ectoderm development (EED), the core scaffold subunit of PRC2 and as an H3K27me3-recognizing protein, has been broadly implicated with PRC2 stabilization and allosterically stimulated PRC2. Accumulating evidences from experimental data indicate that EED-associating epigenetic modifications are indispensable for stem cell maintenance and differentiation into specific cell lineages. In this review, we discuss the most updated advances to summarize the structural architecture of EED and its contributions and underlying mechanisms to mediating lineage differentiation of different stem cells during epigenetic modification to expand our understanding of PRC2.
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Affiliation(s)
- Liuyan Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Feifei Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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8
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Newar K, Abdulla AZ, Salari H, Fanchon E, Jost D. Dynamical modeling of the H3K27 epigenetic landscape in mouse embryonic stem cells. PLoS Comput Biol 2022; 18:e1010450. [PMID: 36054209 PMCID: PMC9477427 DOI: 10.1371/journal.pcbi.1010450] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 09/15/2022] [Accepted: 07/28/2022] [Indexed: 01/02/2023] Open
Abstract
The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27) plays central roles in the silencing of many lineage-specific genes during development. Recent experimental evidence suggested that the recruitment of histone modifying enzymes like the Polycomb repressive complex 2 (PRC2) at specific sites and their spreading capacities from these sites are key to the establishment and maintenance of a proper epigenomic landscape around Polycomb-target genes. Here, to test whether such mechanisms, as a minimal set of qualitative rules, are quantitatively compatible with data, we developed a mathematical model that can predict the locus-specific distributions of H3K27 modifications based on previous biochemical knowledge. Within the biological context of mouse embryonic stem cells, our model showed quantitative agreement with experimental profiles of H3K27 acetylation and methylation around Polycomb-target genes in wild-type and mutants. In particular, we demonstrated the key role of the reader-writer module of PRC2 and of the competition between the binding of activating and repressing enzymes in shaping the H3K27 landscape around transcriptional start sites. The predicted dynamics of establishment and maintenance of the repressive trimethylated H3K27 state suggest a slow accumulation, in perfect agreement with experiments. Our approach represents a first step towards a quantitative description of PcG regulation in various cellular contexts and provides a generic framework to better characterize epigenetic regulation in normal or disease situations.
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Affiliation(s)
- Kapil Newar
- Univ Grenoble Alpes, CNRS, TIMC laboratory, UMR 5525, Grenoble, France
| | - Amith Zafal Abdulla
- Laboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Université Claude Bernard Lyon 1, Lyon, France
| | - Hossein Salari
- Laboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Université Claude Bernard Lyon 1, Lyon, France
| | - Eric Fanchon
- Univ Grenoble Alpes, CNRS, TIMC laboratory, UMR 5525, Grenoble, France
| | - Daniel Jost
- Univ Grenoble Alpes, CNRS, TIMC laboratory, UMR 5525, Grenoble, France
- Laboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Université Claude Bernard Lyon 1, Lyon, France
- * E-mail:
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Verma A, Arya R, Brahmachari V. Identification of a polycomb responsive region in human HoxA cluster and its long-range interaction with polycomb enriched genomic regions. Gene 2022; 845:146832. [PMID: 36007803 DOI: 10.1016/j.gene.2022.146832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/04/2022]
Abstract
Polycomb and Trithorax group proteins (PcG, TrxG) epigenetically regulate developmental genes. These proteins bind with specific DNA elements, the Polycomb Response Element (PRE). Apart from mutations in polycomb/ trithorax proteins, altered cis-elements like PRE underlie the modified function and thus disease etiology. PREs are well studied in Drosophila, while only a few human PREs have been reported. We have identified a polycomb responsive DNA element, hPRE-HoxA3, in the intron of the HoxA3 gene. The hPRE-HoxA3 represses luciferase reporter activity in a PcG-dependent manner. The endogenous hPRE-HoxA3 element recruits PcG proteins and is enriched with repressive H3K27me3 marks, demonstrating that hPRE-HoxA3 is a part of the PcG-dependent gene regulatory network. Furthermore, it interacts with D11-12, the well-known PRE in the human Hox cluster. hPRE-Hox3 is a part of the 3-dimensional chromosomal domain organization as it is involved in the long-range interaction with other PcG enriched regions of Hox A, B, C, and D clusters.
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Affiliation(s)
- Akanksha Verma
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India.
| | - Richa Arya
- Current address- Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
| | - Vani Brahmachari
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India
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The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development. EPIGENOMES 2022; 6:epigenomes6030023. [PMID: 35997369 PMCID: PMC9397020 DOI: 10.3390/epigenomes6030023] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Embryonic development is a highly intricate and complex process. Different regulatory mechanisms cooperatively dictate the fate of cells as they progress from pluripotent stem cells to terminally differentiated cell types in tissues. A crucial regulator of these processes is the Polycomb Repressive Complex 2 (PRC2). By catalyzing the mono-, di-, and tri-methylation of lysine residues on histone H3 tails (H3K27me3), PRC2 compacts chromatin by cooperating with Polycomb Repressive Complex 1 (PRC1) and represses transcription of target genes. Proteomic and biochemical studies have revealed two variant complexes of PRC2, namely PRC2.1 which consists of the core proteins (EZH2, SUZ12, EED, and RBBP4/7) interacting with one of the Polycomb-like proteins (MTF2, PHF1, PHF19), and EPOP or PALI1/2, and PRC2.2 which contains JARID2 and AEBP2 proteins. MTF2 and JARID2 have been discovered to have crucial roles in directing and recruiting PRC2 to target genes for repression in embryonic stem cells (ESCs). Following these findings, recent work in the field has begun to explore the roles of different PRC2 variant complexes during different stages of embryonic development, by examining molecular phenotypes of PRC2 mutants in both in vitro (2D and 3D differentiation) and in vivo (knock-out mice) assays, analyzed with modern single-cell omics and biochemical assays. In this review, we discuss the latest findings that uncovered the roles of different PRC2 proteins during cell-fate and lineage specification and extrapolate these findings to define a developmental roadmap for different flavors of PRC2 regulation during mammalian embryonic development.
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11
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Peedicayil J. The relevance of polycomb group proteins to the development of psychiatric disorders. Front Cell Dev Biol 2022; 10:927833. [PMID: 35938156 PMCID: PMC9354779 DOI: 10.3389/fcell.2022.927833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/28/2022] [Indexed: 11/18/2022] Open
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Cheng Q, Xie H, Zhang X, Wang M, Bi C, Wang Q, Wang R, Fang M. An essential role for
PTIP
in mediating Hox gene regulation along
PcG
and
trxG
pathways. FEBS J 2022; 289:6324-6341. [DOI: 10.1111/febs.16541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/19/2022] [Accepted: 05/31/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Qian Cheng
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
| | - Hao Xie
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
| | - Xiao‐Yan Zhang
- Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Ming‐Ying Wang
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
| | - Cai‐Li Bi
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
- Institute of Translational Medicine, Medical College Yangzhou University China
| | - Qiang Wang
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
| | - Rui Wang
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
| | - Ming Fang
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases Southeast University Nanjing China
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13
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State of Drosophila melanogaster Ovaries after a Full Cycle of Gametogenesis under Microgravity Modeling: Cellular Respiration and the Content of Cytoskeletal Proteins. Int J Mol Sci 2021; 22:ijms22179234. [PMID: 34502148 PMCID: PMC8431292 DOI: 10.3390/ijms22179234] [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: 08/06/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
The effect of weightlessness on gametogenesis and the functional state of female germ cells are still poorly understood. We studied the ovaries of Drosophila melanogaster, the full development cycle of which (from zygote to sexually mature adults) passed under simulated microgravity by a random positioning machine. The rate of cellular respiration was studied by polarography as a parameter reflecting the functional state of mitochondria. The content of cytoskeletal proteins and histones was determined using Western blotting. The relative content of mRNA was determined using qRT-PCR. The results obtained indicated an increase in the rate of cellular respiration under simulated microgravity conditions during the full cycle of gametogenesis in Drosophila melanogaster due to complex I of the respiratory chain. In addition, an increase in the contents of actin cytoskeleton components was observed against the background of an increase in the mRNA content of the cytoskeleton’s encoding genes. Moreover, we observed an increase in the relative content of histone H3 acetylated at Lys9 and Lys27, which may explain the increase in the expression of cytoskeletal genes. In conclusion, the formation of an adaptive pattern of functioning of the Drosophila melanogaster ovaries that developed under simulated microgravity includes structural and functional changes and epigenetic regulation.
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14
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Ornelas-Ayala D, Garay-Arroyo A, García-Ponce B, R. Álvarez-Buylla E, Sanchez MDLP. The Epigenetic Faces of ULTRAPETALA1. FRONTIERS IN PLANT SCIENCE 2021; 12:637244. [PMID: 33719312 PMCID: PMC7947857 DOI: 10.3389/fpls.2021.637244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/21/2021] [Indexed: 05/27/2023]
Abstract
ULTRAPETALA1 (ULT1) is a versatile plant-exclusive protein, initially described as a trithorax group (TrxG) factor that regulates transcriptional activation and counteracts polycomb group (PcG) repressor function. As part of TrxG, ULT1 interacts with ARABIDOPSIS TRITHORAX1 (ATX1) to regulate H3K4me3 activation mark deposition. However, our recent studies indicate that ULT1 can also act independently of ATX1. Moreover, the ULT1 ability to interact with transcription factors (TFs) and PcG proteins indicates that it is a versatile protein with other roles. Therefore, in this work we revised recent information about the function of Arabidopsis ULT1 to understand the roles of ULT1 in plant development. Furthermore, we discuss the molecular mechanisms of ULT1, highlighting its epigenetic role, in which ULT1 seems to have characteristics of an epigenetic molecular switch that regulates repression and activation processes via TrxG and PcG complexes.
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Affiliation(s)
- Diego Ornelas-Ayala
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM, Mexico City, Mexico
| | - Adriana Garay-Arroyo
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM, Mexico City, Mexico
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Berenice García-Ponce
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM, Mexico City, Mexico
| | - Elena R. Álvarez-Buylla
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM, Mexico City, Mexico
- Centro de Ciencias de la Complejidad (C3), Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - María de la Paz Sanchez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM, Mexico City, Mexico
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15
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Khan S, Sowpati DT, Srinivasan A, Soujanya M, Mishra RK. Long-Read Genome Sequencing and Assembly of Leptopilina boulardi: A Specialist Drosophila Parasitoid. G3 (BETHESDA, MD.) 2020; 10:1485-1494. [PMID: 32217632 PMCID: PMC7202025 DOI: 10.1534/g3.120.401151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
Leptopilinaboulardi (Hymenoptera: Figitidae) is a specialist parasitoid of Drosophila The Drosophila-Leptopilina system has emerged as a suitable model for understanding several aspects of host-parasitoid biology. However, a good quality genome of the wasp counterpart was lacking. Here, we report a whole-genome assembly of L. boulardi to bring it in the scope of the applied and fundamental research on Drosophila parasitoids with access to epigenomics and genome editing tools. The 375Mb draft genome has an N50 of 275Kb with 6315 scaffolds >500bp and encompasses >95% complete BUSCOs. Using a combination of ab-initio and RNA-Seq based methods, 25259 protein-coding genes were predicted and 90% (22729) of them could be annotated with at least one function. We demonstrate the quality of the assembled genome by recapitulating the phylogenetic relationship of L. boulardi with other Hymenopterans. The key developmental regulators like Hox genes and sex determination genes are well conserved in L. boulardi, and so is the basic toolkit for epigenetic regulation. The search for epigenetic regulators has also revealed that L. boulardi genome possesses DNMT1 (maintenance DNA methyltransferase), DNMT2 (tRNA methyltransferase) but lacks the de novo DNA methyltransferase (DNMT3). Also, the heterochromatin protein 1 family appears to have expanded as compared to other hymenopterans. The draft genome of L. boulardi (Lb17) will expedite the research on Drosophila parasitoids. This genome resource and early indication of epigenetic aspects in its specialization make it an interesting system to address a variety of questions on host-parasitoid biology.
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Affiliation(s)
- Shagufta Khan
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad - 500007, Telangana, India
| | - Divya Tej Sowpati
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad - 500007, Telangana, India
| | - Arumugam Srinivasan
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad - 500007, Telangana, India
| | - Mamilla Soujanya
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad - 500007, Telangana, India
| | - Rakesh K Mishra
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad - 500007, Telangana, India
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16
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Abstract
As the process that silences gene expression ensues during development, the stage is set for the activity of Polycomb-repressive complex 2 (PRC2) to maintain these repressed gene profiles. PRC2 catalyzes a specific histone posttranslational modification (hPTM) that fosters chromatin compaction. PRC2 also facilitates the inheritance of this hPTM through its self-contained "write and read" activities, key to preserving cellular identity during cell division. As these changes in gene expression occur without changes in DNA sequence and are inherited, the process is epigenetic in scope. Mutants of mammalian PRC2 or of its histone substrate contribute to the cancer process and other diseases, and research into these aberrant pathways is yielding viable candidates for therapeutic targeting. The effectiveness of PRC2 hinges on its being recruited to the proper chromatin sites; however, resolving the determinants to this process in the mammalian case was not straightforward and thus piqued the interest of many in the field. Here, we chronicle the latest advances toward exposing mammalian PRC2 and its high maintenance.
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Affiliation(s)
- Jia-Ray Yu
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
| | - Chul-Hwan Lee
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
| | - Ozgur Oksuz
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
| | - James M Stafford
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
| | - Danny Reinberg
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
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17
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Piacentini L, Marchetti M, Bucciarelli E, Casale AM, Cappucci U, Bonifazi P, Renda F, Fanti L. A role of the Trx-G complex in Cid/CENP-A deposition at Drosophila melanogaster centromeres. Chromosoma 2019; 128:503-520. [PMID: 31203392 DOI: 10.1007/s00412-019-00711-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 05/07/2019] [Accepted: 05/30/2019] [Indexed: 12/23/2022]
Abstract
Centromeres are epigenetically determined chromatin structures that specify the assembly site of the kinetochore, the multiprotein machinery that binds microtubules and mediates chromosome segregation during mitosis and meiosis. The centromeric protein A (CENP-A) and its Drosophila orthologue centromere identifier (Cid) are H3 histone variants that replace the canonical H3 histone in centromeric nucleosomes of eukaryotes. CENP-A/Cid is required for recruitment of other centromere and kinetochore proteins and its deficiency disrupts chromosome segregation. Despite the many components that are known to cooperate in centromere function, the complete network of factors involved in CENP-A recruitment remains to be defined. In Drosophila, the Trx-G proteins localize along the heterochromatin with specific patterns and some of them localize to the centromeres of all chromosomes. Here, we show that the Trx, Ash1, and CBP proteins are required for the correct chromosome segregation and that Ash1 and CBP mediate for Cid/CENP-A recruitment at centromeres through post-translational histone modifications. We found that centromeric H3 histone is consistently acetylated in K27 by CBP and that nej and ash1 silencing respectively causes a decrease in H3K27 acetylation and H3K4 methylation along with an impairment of Cid loading.
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Affiliation(s)
- Lucia Piacentini
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy
| | - Marcella Marchetti
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy
| | | | - Assunta Maria Casale
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy
| | - Ugo Cappucci
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy
| | - Paolo Bonifazi
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy
| | - Fioranna Renda
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy.,Wadsworth Center, New York State Department of Health, Albany, NY, 12201, USA
| | - Laura Fanti
- Istituto Pasteur Italia, Dipartimento di Biologia e Biotecnologie "Charles Darwin", Università "Sapienza", Rome, Italy.
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18
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Aylwin CF, Toro CA, Shirtcliff E, Lomniczi A. Emerging Genetic and Epigenetic Mechanisms Underlying Pubertal Maturation in Adolescence. JOURNAL OF RESEARCH ON ADOLESCENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR RESEARCH ON ADOLESCENCE 2019; 29:54-79. [PMID: 30869843 DOI: 10.1111/jora.12385] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The adolescent transition begins with the onset of puberty which, upstream in the brain, is initiated by the gonadotropin-releasing hormone (GnRH) pulse generator that activates the release of peripheral sex hormones. Substantial research in human and animal models has revealed a myriad of cellular networks and heritable genes that control the GnRH pulse generator allowing the individual to begin the process of reproductive competence and sexual maturation. Here, we review the latest knowledge in neuroendocrine pubertal research with emphasis on genetic and epigenetic mechanisms underlying the pubertal transition.
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19
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Adhikary G, Grun D, Alexander HR, Friedberg JS, Xu W, Keillor JW, Kandasamy S, Eckert RL. Transglutaminase is a mesothelioma cancer stem cell survival protein that is required for tumor formation. Oncotarget 2018; 9:34495-34505. [PMID: 30349644 PMCID: PMC6195372 DOI: 10.18632/oncotarget.26130] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 09/08/2018] [Indexed: 12/26/2022] Open
Abstract
Mesothelioma is a rare cancer of the mesothelial cell layer of the pleura, peritoneum, pericardium and tunica vaginalis. It is typically caused by asbestos, notoriously resistant to chemotherapy and generally considered incurable with a poor life expectancy. Transglutaminase 2 (TG2), a GTP binding regulatory protein, is an important cancer stem cell survival and therapy resistance factor. We show that TG2 is highly expressed in human mesothelioma tumors and in mesothelioma cancer stem cells (MCS cells). TG2 knockdown or TG2 inhibitor treatment reduces MCS cell spheroid formation, matrigel invasion, migration and tumor formation. Time to tumor first appearance is doubled in TG2 knockout cells as compared to wild-type. In addition, TG2 loss is associated with reduced expression of stemness, and epithelial mesenchymal transition markers, and enhanced apoptosis. These studies indicate that TG2 is an important MCS cell survival protein and suggest that TG2 may serve as a mesothelioma cancer stem cell therapy target.
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Affiliation(s)
- Gautam Adhikary
- 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Daniel Grun
- 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - H. Richard Alexander
- 7 Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - Joseph S. Friedberg
- 4 Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA,5 Department of Surgery and Division of General and Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wen Xu
- 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | - Sivaveera Kandasamy
- 5 Department of Surgery and Division of General and Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Richard L. Eckert
- 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA,2 Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA,3 Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA,4 Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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20
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Dardalhon-Cuménal D, Deraze J, Dupont CA, Ribeiro V, Coléno-Costes A, Pouch J, Le Crom S, Thomassin H, Debat V, Randsholt NB, Peronnet F. Cyclin G and the Polycomb Repressive complexes PRC1 and PR-DUB cooperate for developmental stability. PLoS Genet 2018; 14:e1007498. [PMID: 29995890 PMCID: PMC6065198 DOI: 10.1371/journal.pgen.1007498] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 07/27/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022] Open
Abstract
In Drosophila, ubiquitous expression of a short Cyclin G isoform generates extreme developmental noise estimated by fluctuating asymmetry (FA), providing a model to tackle developmental stability. This transcriptional cyclin interacts with chromatin regulators of the Enhancer of Trithorax and Polycomb (ETP) and Polycomb families. This led us to investigate the importance of these interactions in developmental stability. Deregulation of Cyclin G highlights an organ intrinsic control of developmental noise, linked to the ETP-interacting domain, and enhanced by mutations in genes encoding members of the Polycomb Repressive complexes PRC1 and PR-DUB. Deep-sequencing of wing imaginal discs deregulating CycG reveals that high developmental noise correlates with up-regulation of genes involved in translation and down-regulation of genes involved in energy production. Most Cyclin G direct transcriptional targets are also direct targets of PRC1 and RNAPolII in the developing wing. Altogether, our results suggest that Cyclin G, PRC1 and PR-DUB cooperate for developmental stability.
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Affiliation(s)
- Delphine Dardalhon-Cuménal
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Jérôme Deraze
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Camille A. Dupont
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Valérie Ribeiro
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Anne Coléno-Costes
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Juliette Pouch
- Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale
supérieure, CNRS, INSERM, PSL Université Paris Paris, France
| | - Stéphane Le Crom
- Institut de biologie de l’Ecole normale supérieure (IBENS), Ecole normale
supérieure, CNRS, INSERM, PSL Université Paris Paris, France
- Sorbonne Université, Univ Antilles, Univ Nice Sophia Antipolis, CNRS,
Evolution Paris Seine—Institut de Biologie Paris Seine (EPS - IBPS), Paris,
France
| | - Hélène Thomassin
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Vincent Debat
- Institut de Systematique, Evolution, Biodiversité ISYEB UMR 7205, MNHN,
CNRS, Sorbonne Université, EPHE, Muséum national d'Histoire naturelle, Sorbonne
Universités, Paris, France
| | - Neel B. Randsholt
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
| | - Frédérique Peronnet
- Sorbonne Université, Centre National de la Recherche Scientifique (CNRS),
Institut de Biologie Paris-Seine (IBPS), Laboratory of Developmental Biology
(LBD), Paris, France
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21
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Zhu J, Ordway AJ, Weber L, Buddika K, Kumar JP. Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye. Development 2018; 145:dev160754. [PMID: 29530880 PMCID: PMC5963869 DOI: 10.1242/dev.160754] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 03/01/2018] [Indexed: 01/01/2023]
Abstract
How different cells and tissues commit to and determine their fates has been a central question in developmental biology since the seminal embryological experiments conducted by Wilhelm Roux and Hans Driesch in sea urchins and frogs. Here, we demonstrate that Polycomb group (PcG) proteins maintain Drosophila eye specification by suppressing the activation of alternative fate choices. The loss of PcG in the developing eye results in a cellular reprogramming event in which the eye is redirected to a wing fate. This fate transformation occurs with either the individual loss of Polycomb proteins or the simultaneous reduction of the Pleiohomeotic repressive complex and Pax6. Interestingly, the requirement for retinal selector genes is limited to Pax6, as the removal of more downstream members does not lead to the eye-wing transformation. We also show that distinct PcG complexes are required during different developmental windows throughout eye formation. These findings build on earlier observations that the eye can be reprogrammed to initiate head epidermis, antennal and leg development.
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Affiliation(s)
- Jinjin Zhu
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Alison J Ordway
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Lena Weber
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Kasun Buddika
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Justin P Kumar
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
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22
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Huang Y, Chen DH, Liu BY, Shen WH, Ruan Y. Conservation and diversification of polycomb repressive complex 2 (PRC2) proteins in the green lineage. Brief Funct Genomics 2017; 16:106-119. [PMID: 27032420 DOI: 10.1093/bfgp/elw007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The polycomb group (PcG) proteins are key epigenetic regulators of gene expression in animals and plants. They act in multiprotein complexes, of which the best characterized is the polycomb repressive complex 2 (PRC2), which catalyses the trimethylation of histone H3 at lysine 27 (H3K27me3) at chromatin targets. In Arabidopsis thaliana, PRC2 proteins are involved in the regulation of diverse developmental processes, including cell fate determination, vegetative growth and development, flowering time control and embryogenesis. Here, we systematically analysed the evolutionary conservation and diversification of PRC2 components in lower and higher plants. We searched for and identified PRC2 homologues from the sequenced genomes of several green lineage species, from the unicellular green alga Ostreococcus lucimarinus to more complicated angiosperms. We found that some PRC2 core components, e.g. E(z), ESC/FIE and MSI/p55, are ancient and have multiplied coincidently with multicellular evolution. For one component, some members are newly formed, especially in the Cruciferae. During evolution, higher plants underwent copy number multiplication of various PRC2 components, which occurred independently for each component, without any obvious co-amplification of PRC2 members. Among the amplified members, usually one was well-conserved and the others were more diversified. Gene amplification occurred at different times for different PcG members during green lineage evolution. Certain PRC2 core components or members of them were highly conserved. Our study provides an insight into the evolutionary conservation and diversification of PcG proteins and may guide future functional characterization of these important epigenetic regulators in plants other than Arabidopsis.
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Affiliation(s)
- Yong Huang
- College of Bioscience and Biotechnology, International Associated Laboratory of CNRS-FU-HAU On Plant Epigenome Research, Hunan Agricultural University, Changsha, China.,Key Laboratory of Education, Department of Hunan Province On Plant Genetics and Molecular Biology, Hunan Agricultural University, Changsha, China
| | - Dong-Hong Chen
- College of Bioscience and Biotechnology, International Associated Laboratory of CNRS-FU-HAU On Plant Epigenome Research, Hunan Agricultural University, Changsha, China.,Key Laboratory of Education, Department of Hunan Province On Plant Genetics and Molecular Biology, Hunan Agricultural University, Changsha, China
| | - Bo-Yu Liu
- Hunan Provincial Key Laboratory of Crop Germplasm Innovation and Utilization, Hunan Agricultural University, Changsha, China
| | - Wen-Hui Shen
- College of Bioscience and Biotechnology, International Associated Laboratory of CNRS-FU-HAU On Plant Epigenome Research, Hunan Agricultural University, Changsha, China.,Institut de Biologie Moléculaire Des Plantes Du CNRS, Université de Strasbourg, 12 Rue Du Général Zimmer, Strasbourg Cedex, France
| | - Ying Ruan
- College of Bioscience and Biotechnology, International Associated Laboratory of CNRS-FU-HAU On Plant Epigenome Research, Hunan Agricultural University, Changsha, China.,Key Laboratory of Education, Department of Hunan Province On Plant Genetics and Molecular Biology, Hunan Agricultural University, Changsha, China.,Hunan Provincial Key Laboratory of Crop Germplasm Innovation and Utilization, Hunan Agricultural University, Changsha, China
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23
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Kang H, Jung YL, McElroy KA, Zee BM, Wallace HA, Woolnough JL, Park PJ, Kuroda MI. Bivalent complexes of PRC1 with orthologs of BRD4 and MOZ/MORF target developmental genes in Drosophila. Genes Dev 2017; 31:1988-2002. [PMID: 29070704 PMCID: PMC5710143 DOI: 10.1101/gad.305987.117] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 09/28/2017] [Indexed: 02/05/2023]
Abstract
Kang et al. confirm PRC1–Br140 and PRC1–Fs(1)h interactions and identify their genomic binding sites. PRC1–Br140 bind developmental genes in fly embryos, with analogous co-occupancy of PRC1 and BRD1 at bivalent loci in human ES cells. Regulatory decisions in Drosophila require Polycomb group (PcG) proteins to maintain the silent state and Trithorax group (TrxG) proteins to oppose silencing. Since PcG and TrxG are ubiquitous and lack apparent sequence specificity, a long-standing model is that targeting occurs via protein interactions; for instance, between repressors and PcG proteins. Instead, we found that Pc-repressive complex 1 (PRC1) purifies with coactivators Fs(1)h [female sterile (1) homeotic] and Enok/Br140 during embryogenesis. Fs(1)h is a TrxG member and the ortholog of BRD4, a bromodomain protein that binds to acetylated histones and is a key transcriptional coactivator in mammals. Enok and Br140, another bromodomain protein, are orthologous to subunits of a mammalian MOZ/MORF acetyltransferase complex. Here we confirm PRC1–Br140 and PRC1–Fs(1)h interactions and identify their genomic binding sites. PRC1–Br140 bind developmental genes in fly embryos, with analogous co-occupancy of PRC1 and a Br140 ortholog, BRD1, at bivalent loci in human embryonic stem (ES) cells. We propose that identification of PRC1–Br140 “bivalent complexes” in fly embryos supports and extends the bivalency model posited in mammalian cells, in which the coexistence of H3K4me3 and H3K27me3 at developmental promoters represents a poised transcriptional state. We further speculate that local competition between acetylation and deacetylation may play a critical role in the resolution of bivalent protein complexes during development.
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Affiliation(s)
- Hyuckjoon Kang
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Youngsook L Jung
- Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Kyle A McElroy
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.,Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
| | - Barry M Zee
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Heather A Wallace
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Jessica L Woolnough
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Peter J Park
- Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Mitzi I Kuroda
- Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
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Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. Cell 2017; 171:34-57. [DOI: 10.1016/j.cell.2017.08.002] [Citation(s) in RCA: 611] [Impact Index Per Article: 76.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/17/2017] [Accepted: 08/01/2017] [Indexed: 01/05/2023]
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Leung W, Shaffer CD, Chen EJ, Quisenberry TJ, Ko K, Braverman JM, Giarla TC, Mortimer NT, Reed LK, Smith ST, Robic S, McCartha SR, Perry DR, Prescod LM, Sheppard ZA, Saville KJ, McClish A, Morlock EA, Sochor VR, Stanton B, Veysey-White IC, Revie D, Jimenez LA, Palomino JJ, Patao MD, Patao SM, Himelblau ET, Campbell JD, Hertz AL, McEvilly MF, Wagner AR, Youngblom J, Bedi B, Bettincourt J, Duso E, Her M, Hilton W, House S, Karimi M, Kumimoto K, Lee R, Lopez D, Odisho G, Prasad R, Robbins HL, Sandhu T, Selfridge T, Tsukashima K, Yosif H, Kokan NP, Britt L, Zoellner A, Spana EP, Chlebina BT, Chong I, Friedman H, Mammo DA, Ng CL, Nikam VS, Schwartz NU, Xu TQ, Burg MG, Batten SM, Corbeill LM, Enoch E, Ensign JJ, Franks ME, Haiker B, Ingles JA, Kirkland LD, Lorenz-Guertin JM, Matthews J, Mittig CM, Monsma N, Olson KJ, Perez-Aragon G, Ramic A, Ramirez JR, Scheiber C, Schneider PA, Schultz DE, Simon M, Spencer E, Wernette AC, Wykle ME, Zavala-Arellano E, McDonald MJ, Ostby K, Wendland P, DiAngelo JR, Ceasrine AM, Cox AH, Docherty JEB, Gingras RM, Grieb SM, Pavia MJ, Personius CL, Polak GL, Beach DL, Cerritos HL, et alLeung W, Shaffer CD, Chen EJ, Quisenberry TJ, Ko K, Braverman JM, Giarla TC, Mortimer NT, Reed LK, Smith ST, Robic S, McCartha SR, Perry DR, Prescod LM, Sheppard ZA, Saville KJ, McClish A, Morlock EA, Sochor VR, Stanton B, Veysey-White IC, Revie D, Jimenez LA, Palomino JJ, Patao MD, Patao SM, Himelblau ET, Campbell JD, Hertz AL, McEvilly MF, Wagner AR, Youngblom J, Bedi B, Bettincourt J, Duso E, Her M, Hilton W, House S, Karimi M, Kumimoto K, Lee R, Lopez D, Odisho G, Prasad R, Robbins HL, Sandhu T, Selfridge T, Tsukashima K, Yosif H, Kokan NP, Britt L, Zoellner A, Spana EP, Chlebina BT, Chong I, Friedman H, Mammo DA, Ng CL, Nikam VS, Schwartz NU, Xu TQ, Burg MG, Batten SM, Corbeill LM, Enoch E, Ensign JJ, Franks ME, Haiker B, Ingles JA, Kirkland LD, Lorenz-Guertin JM, Matthews J, Mittig CM, Monsma N, Olson KJ, Perez-Aragon G, Ramic A, Ramirez JR, Scheiber C, Schneider PA, Schultz DE, Simon M, Spencer E, Wernette AC, Wykle ME, Zavala-Arellano E, McDonald MJ, Ostby K, Wendland P, DiAngelo JR, Ceasrine AM, Cox AH, Docherty JEB, Gingras RM, Grieb SM, Pavia MJ, Personius CL, Polak GL, Beach DL, Cerritos HL, Horansky EA, Sharif KA, Moran R, Parrish S, Bickford K, Bland J, Broussard J, Campbell K, Deibel KE, Forka R, Lemke MC, Nelson MB, O'Keeffe C, Ramey SM, Schmidt L, Villegas P, Jones CJ, Christ SL, Mamari S, Rinaldi AS, Stity G, Hark AT, Scheuerman M, Silver Key SC, McRae BD, Haberman AS, Asinof S, Carrington H, Drumm K, Embry T, McGuire R, Miller-Foreman D, Rosen S, Safa N, Schultz D, Segal M, Shevin Y, Svoronos P, Vuong T, Skuse G, Paetkau DW, Bridgman RK, Brown CM, Carroll AR, Gifford FM, Gillespie JB, Herman SE, Holtcamp KL, Host MA, Hussey G, Kramer DM, Lawrence JQ, Martin MM, Niemiec EN, O'Reilly AP, Pahl OA, Quintana G, Rettie EAS, Richardson TL, Rodriguez AE, Rodriguez MO, Schiraldi L, Smith JJ, Sugrue KF, Suriano LJ, Takach KE, Vasquez AM, Velez X, Villafuerte EJ, Vives LT, Zellmer VR, Hauke J, Hauser CR, Barker K, Cannon L, Parsamian P, Parsons S, Wichman Z, Bazinet CW, Johnson DE, Bangura A, Black JA, Chevee V, Einsteen SA, Hilton SK, Kollmer M, Nadendla R, Stamm J, Fafara-Thompson AE, Gygi AM, Ogawa EE, Van Camp M, Kocsisova Z, Leatherman JL, Modahl CM, Rubin MR, Apiz-Saab SS, Arias-Mejias SM, Carrion-Ortiz CF, Claudio-Vazquez PN, Espada-Green DM, Feliciano-Camacho M, Gonzalez-Bonilla KM, Taboas-Arroyo M, Vargas-Franco D, Montañez-Gonzalez R, Perez-Otero J, Rivera-Burgos M, Rivera-Rosario FJ, Eisler HL, Alexander J, Begley SK, Gabbard D, Allen RJ, Aung WY, Barshop WD, Boozalis A, Chu VP, Davis JS, Duggal RN, Franklin R, Gavinski K, Gebreyesus H, Gong HZ, Greenstein RA, Guo AD, Hanson C, Homa KE, Hsu SC, Huang Y, Huo L, Jacobs S, Jia S, Jung KL, Wai-Chee Kong S, Kroll MR, Lee BM, Lee PF, Levine KM, Li AS, Liu C, Liu MM, Lousararian AP, Lowery PB, Mallya AP, Marcus JE, Ng PC, Nguyen HP, Patel R, Precht H, Rastogi S, Sarezky JM, Schefkind A, Schultz MB, Shen D, Skorupa T, Spies NC, Stancu G, Vivian Tsang HM, Turski AL, Venkat R, Waldman LE, Wang K, Wang T, Wei JW, Wu DY, Xiong DD, Yu J, Zhou K, McNeil GP, Fernandez RW, Menzies PG, Gu T, Buhler J, Mardis ER, Elgin SCR. Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element. G3 (BETHESDA, MD.) 2017; 7:2439-2460. [PMID: 28667019 PMCID: PMC5555453 DOI: 10.1534/g3.117.040907] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 04/03/2017] [Indexed: 11/24/2022]
Abstract
The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5' ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains.
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Affiliation(s)
- Wilson Leung
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | | | - Elizabeth J Chen
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | | | - Kevin Ko
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - John M Braverman
- Department of Biology, Saint Joseph's University, Philadelphia, PA 19131
| | | | - Nathan T Mortimer
- School of Biological Sciences, Illinois State University, Normal, IL 61790
| | - Laura K Reed
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35401
| | - Sheryl T Smith
- Department of Biology, Arcadia University, Glenside, PA 19038
| | - Srebrenka Robic
- Department of Biology, Agnes Scott College, Decatur, GA 30030
| | | | | | | | | | - Ken J Saville
- Department of Biology, Albion College, Albion, MI 49224
| | | | | | | | | | | | - Dennis Revie
- Department of Biology, California Lutheran University, Thousand Oaks, CA 91360
| | - Luis A Jimenez
- Department of Biology, California Lutheran University, Thousand Oaks, CA 91360
| | - Jennifer J Palomino
- Department of Biology, California Lutheran University, Thousand Oaks, CA 91360
| | - Melissa D Patao
- Department of Biology, California Lutheran University, Thousand Oaks, CA 91360
| | - Shane M Patao
- Department of Biology, California Lutheran University, Thousand Oaks, CA 91360
| | - Edward T Himelblau
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405
| | - Jaclyn D Campbell
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405
| | - Alexandra L Hertz
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405
| | - Maddison F McEvilly
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405
| | - Allison R Wagner
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405
| | - James Youngblom
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Baljit Bedi
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Jeffery Bettincourt
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Erin Duso
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Maiye Her
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - William Hilton
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Samantha House
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Masud Karimi
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Kevin Kumimoto
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Rebekah Lee
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Darryl Lopez
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - George Odisho
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Ricky Prasad
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Holly Lyn Robbins
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Tanveer Sandhu
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Tracy Selfridge
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Kara Tsukashima
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Hani Yosif
- Department of Biology, California State University, Stanislaus, Turlock, CA 95382
| | - Nighat P Kokan
- Department of Natural Sciences, Cardinal Stritch University, Milwaukee, WI 53217
| | - Latia Britt
- Department of Natural Sciences, Cardinal Stritch University, Milwaukee, WI 53217
| | - Alycia Zoellner
- Department of Natural Sciences, Cardinal Stritch University, Milwaukee, WI 53217
| | - Eric P Spana
- Department of Biology, Duke University, Durham, NC 27708
| | - Ben T Chlebina
- Department of Biology, Duke University, Durham, NC 27708
| | - Insun Chong
- Department of Biology, Duke University, Durham, NC 27708
| | | | - Danny A Mammo
- Department of Biology, Duke University, Durham, NC 27708
| | - Chun L Ng
- Department of Biology, Duke University, Durham, NC 27708
| | | | | | - Thomas Q Xu
- Department of Biology, Duke University, Durham, NC 27708
| | - Martin G Burg
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Spencer M Batten
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Lindsay M Corbeill
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Erica Enoch
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Jesse J Ensign
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Mary E Franks
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Breanna Haiker
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Judith A Ingles
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Lyndsay D Kirkland
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Joshua M Lorenz-Guertin
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Jordan Matthews
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Cody M Mittig
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Nicholaus Monsma
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Katherine J Olson
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Guillermo Perez-Aragon
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Alen Ramic
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Jordan R Ramirez
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Christopher Scheiber
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Patrick A Schneider
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Devon E Schultz
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Matthew Simon
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Eric Spencer
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Adam C Wernette
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Maxine E Wykle
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Elizabeth Zavala-Arellano
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Mitchell J McDonald
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Kristine Ostby
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | - Peter Wendland
- Departments of Biomedical Sciences and Cell and Molecular Biology, Grand Valley State University, Allendale, MI 49401
| | | | | | - Amanda H Cox
- Department of Biology, Hofstra University, Hempstead, NY 11549
| | | | | | | | - Michael J Pavia
- Department of Biology, Hofstra University, Hempstead, NY 11549
| | | | | | - Dale L Beach
- Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909
| | - Heaven L Cerritos
- Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909
| | - Edward A Horansky
- Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909
| | - Karim A Sharif
- Department of Biology, Massasoit Community College, Brockton, MA 02302
| | - Ryan Moran
- Department of Biology, Massasoit Community College, Brockton, MA 02302
| | - Susan Parrish
- Department of Biology, McDaniel College, Westminster, MD 21157
| | | | - Jennifer Bland
- Department of Biology, McDaniel College, Westminster, MD 21157
| | | | - Kerry Campbell
- Department of Biology, McDaniel College, Westminster, MD 21157
| | | | - Richard Forka
- Department of Biology, McDaniel College, Westminster, MD 21157
| | - Monika C Lemke
- Department of Biology, McDaniel College, Westminster, MD 21157
| | - Marlee B Nelson
- Department of Biology, McDaniel College, Westminster, MD 21157
| | | | - S Mariel Ramey
- Department of Biology, McDaniel College, Westminster, MD 21157
| | - Luke Schmidt
- Department of Biology, McDaniel College, Westminster, MD 21157
| | - Paola Villegas
- Department of Biology, McDaniel College, Westminster, MD 21157
| | | | - Stephanie L Christ
- Department of Biological Sciences, Moravian College, Bethlehem, PA 18018
| | - Sami Mamari
- Department of Biological Sciences, Moravian College, Bethlehem, PA 18018
| | - Adam S Rinaldi
- Department of Biological Sciences, Moravian College, Bethlehem, PA 18018
| | - Ghazal Stity
- Department of Biological Sciences, Moravian College, Bethlehem, PA 18018
| | - Amy T Hark
- Department of Biology, Muhlenberg College, Allentown, PA 18104
| | - Mark Scheuerman
- Department of Biology, Muhlenberg College, Allentown, PA 18104
| | - S Catherine Silver Key
- Department of Biological & Biomedical Sciences, North Carolina Central University, Durham, NC 27707
| | - Briana D McRae
- Department of Biological & Biomedical Sciences, North Carolina Central University, Durham, NC 27707
| | | | - Sam Asinof
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | | | - Kelly Drumm
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Terrance Embry
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | | | | | - Stella Rosen
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Nadia Safa
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Darrin Schultz
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Matt Segal
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Yakov Shevin
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | | | - Tam Vuong
- Department of Biology, Oberlin College, Oberlin, OH 44074
| | - Gary Skuse
- Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, Rochester, NY 14623
| | - Don W Paetkau
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | | | - Alicia R Carroll
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | | | - Susan E Herman
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Misha A Host
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | - Gabrielle Hussey
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Joan Q Lawrence
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Ellen N Niemiec
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Olivia A Pahl
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | | | | | | | - Mona O Rodriguez
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | - Laura Schiraldi
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | - Joanna J Smith
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | - Kelsey F Sugrue
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Kaitlyn E Takach
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Ximena Velez
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Laura T Vives
- Department of Biology, Saint Mary's College, Notre Dame, IN 46556
| | | | - Jeanette Hauke
- Department of Biology, Simmons College, Boston, MA 02115
| | - Charles R Hauser
- Bioinformatics Program, St. Edward's University, Austin, TX 78704
| | - Karolyn Barker
- Bioinformatics Program, St. Edward's University, Austin, TX 78704
| | - Laurie Cannon
- Bioinformatics Program, St. Edward's University, Austin, TX 78704
| | | | - Samantha Parsons
- Bioinformatics Program, St. Edward's University, Austin, TX 78704
| | | | | | - Diana E Johnson
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Abubakarr Bangura
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Jordan A Black
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Victoria Chevee
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Sarah A Einsteen
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Sarah K Hilton
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Max Kollmer
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Rahul Nadendla
- Department of Biological Sciences, The George Washington University, Washington, DC 20052
| | - Joyce Stamm
- Department of Biology, University of Evansville, Evansville, IN 47722
| | | | - Amber M Gygi
- Department of Biology, University of Evansville, Evansville, IN 47722
| | - Emmy E Ogawa
- Department of Biology, University of Evansville, Evansville, IN 47722
| | - Matt Van Camp
- Department of Biology, University of Evansville, Evansville, IN 47722
| | - Zuzana Kocsisova
- Department of Biology, University of Evansville, Evansville, IN 47722
| | - Judith L Leatherman
- Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639
| | - Cassie M Modahl
- Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639
| | - Michael R Rubin
- Department of Biology, University of Puerto Rico at Cayey, Cayey, PR 00736
| | - Susana S Apiz-Saab
- Department of Biology, University of Puerto Rico at Cayey, Cayey, PR 00736
| | | | | | | | | | | | | | | | | | | | - Joseph Perez-Otero
- Department of Biology, University of Puerto Rico at Cayey, Cayey, PR 00736
| | | | | | - Heather L Eisler
- Department of Biology, University of the Cumberlands, Williamsburg, KY 40769
| | - Jackie Alexander
- Department of Biology, University of the Cumberlands, Williamsburg, KY 40769
| | - Samatha K Begley
- Department of Biology, University of the Cumberlands, Williamsburg, KY 40769
| | - Deana Gabbard
- Department of Biology, University of the Cumberlands, Williamsburg, KY 40769
| | - Robert J Allen
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Wint Yan Aung
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - William D Barshop
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Amanda Boozalis
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Vanessa P Chu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Jeremy S Davis
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Ryan N Duggal
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Robert Franklin
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Katherine Gavinski
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Heran Gebreyesus
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Henry Z Gong
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Rachel A Greenstein
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Averill D Guo
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Casey Hanson
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Kaitlin E Homa
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Simon C Hsu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Yi Huang
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Lucy Huo
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Sarah Jacobs
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Sasha Jia
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Kyle L Jung
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Sarah Wai-Chee Kong
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Matthew R Kroll
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Brandon M Lee
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Paul F Lee
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Kevin M Levine
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Amy S Li
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Chengyu Liu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Max Mian Liu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Adam P Lousararian
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Peter B Lowery
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Allyson P Mallya
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Joseph E Marcus
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Patrick C Ng
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Hien P Nguyen
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Ruchik Patel
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Hashini Precht
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Suchita Rastogi
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Jonathan M Sarezky
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Adam Schefkind
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Michael B Schultz
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Delia Shen
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Tara Skorupa
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Nicholas C Spies
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Gabriel Stancu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | | | - Alice L Turski
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Rohit Venkat
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Leah E Waldman
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Kaidi Wang
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Tracy Wang
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Jeffrey W Wei
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Dennis Y Wu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - David D Xiong
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Jack Yu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Karen Zhou
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Gerard P McNeil
- Department of Biology, York College / CUNY, Jamaica, NY 11451
| | | | | | - Tingting Gu
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
| | - Jeremy Buhler
- Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130
| | - Elaine R Mardis
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108
| | - Sarah C R Elgin
- Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
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Three-Dimensional Genome Organization and Function in Drosophila. Genetics 2017; 205:5-24. [PMID: 28049701 PMCID: PMC5223523 DOI: 10.1534/genetics.115.185132] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/15/2016] [Indexed: 12/18/2022] Open
Abstract
Understanding how the metazoan genome is used during development and cell differentiation is one of the major challenges in the postgenomic era. Early studies in Drosophila suggested that three-dimensional (3D) chromosome organization plays important regulatory roles in this process and recent technological advances started to reveal connections at the molecular level. Here we will consider general features of the architectural organization of the Drosophila genome, providing historical perspective and insights from recent work. We will compare the linear and spatial segmentation of the fly genome and focus on the two key regulators of genome architecture: insulator components and Polycomb group proteins. With its unique set of genetic tools and a compact, well annotated genome, Drosophila is poised to remain a model system of choice for rapid progress in understanding principles of genome organization and to serve as a proving ground for development of 3D genome-engineering techniques.
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Berenguer E, Bárány I, Solís MT, Pérez-Pérez Y, Risueño MC, Testillano PS. Inhibition of Histone H3K9 Methylation by BIX-01294 Promotes Stress-Induced Microspore Totipotency and Enhances Embryogenesis Initiation. FRONTIERS IN PLANT SCIENCE 2017; 8:1161. [PMID: 28706533 PMCID: PMC5489599 DOI: 10.3389/fpls.2017.01161] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/16/2017] [Indexed: 05/18/2023]
Abstract
Microspore embryogenesis is a process of cell reprogramming, totipotency acquisition and embryogenesis initiation, induced in vitro by stress treatments and widely used in plant breeding for rapid production of doubled-haploids, but its regulating mechanisms are still largely unknown. Increasing evidence has revealed epigenetic reprogramming during microspore embryogenesis, through DNA methylation, but less is known about the involvement of histone modifications. In this study, we have analyzed the dynamics and possible role of histone H3K9 methylation, a major repressive modification, as well as the effects on microspore embryogenesis initiation of BIX-01294, an inhibitor of histone methylation, tested for the first time in plants, in Brassica napus and Hordeum vulgare. Results revealed that microspore reprogramming and initiation of embryogenesis involved a low level of H3K9 methylation. With the progression of embryogenesis, methylation of H3K9 increased, correlating with gene expression profiles of BnHKMT SUVR4-like and BnLSD1-like (writer and eraser enzymes of H3K9me2). At early stages, BIX-01294 promoted cell reprogramming, totipotency and embryogenesis induction, while diminishing bulk H3K9 methylation. DNA methylation was also reduced by short-term BIX-01294 treatment. By contrast, long BIX-01294 treatments hindered embryogenesis progression, indicating that H3K9 methylation is required for embryo differentiation. These findings open up new possibilities to enhance microspore embryogenesis efficiency in recalcitrant species through pharmacological modulation of histone methylation by using BIX-01294.
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Loubière V, Delest A, Thomas A, Bonev B, Schuettengruber B, Sati S, Martinez AM, Cavalli G. Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development. Nat Genet 2016; 48:1436-1442. [PMID: 27643538 PMCID: PMC5407438 DOI: 10.1038/ng.3671] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 08/22/2016] [Indexed: 12/14/2022]
Abstract
Polycomb group proteins form two main complexes, PRC2 and PRC1, which generally coregulate their target genes. Here we show that PRC1 components act as neoplastic tumor suppressors independently of PRC2 function. By mapping the distribution of PRC1 components and trimethylation of histone H3 at Lys27 (H3K27me3) across the genome, we identify a large set of genes that acquire PRC1 in the absence of H3K27me3 in Drosophila larval tissues. These genes massively outnumber canonical targets and are mainly involved in the regulation of cell proliferation, signaling and polarity. Alterations in PRC1 components specifically deregulate this set of genes, whereas canonical targets are derepressed in both PRC1 and PRC2 mutants. In human embryonic stem cells, PRC1 components colocalize with H3K27me3 as in Drosophila embryos, whereas in differentiated cell types they are selectively recruited to a large set of proliferation and signaling-associated genes that lack H3K27me3, suggesting that the redeployment of PRC1 components during development is evolutionarily conserved.
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Affiliation(s)
- Vincent Loubière
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Anna Delest
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Aubin Thomas
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Boyan Bonev
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Bernd Schuettengruber
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Satish Sati
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Anne-Marie Martinez
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
| | - Giacomo Cavalli
- Institute of Human Genetics, UPR1142 CNRS, 141 Rue de la Cardonille, 34396, Montpellier Cedex 5, France
- Universite de Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
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Boureau L, How-Kit A, Teyssier E, Drevensek S, Rainieri M, Joubès J, Stammitti L, Pribat A, Bowler C, Hong Y, Gallusci P. A CURLY LEAF homologue controls both vegetative and reproductive development of tomato plants. PLANT MOLECULAR BIOLOGY 2016; 90:485-501. [PMID: 26846417 DOI: 10.1007/s11103-016-0436-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 01/08/2016] [Indexed: 05/21/2023]
Abstract
The Enhancer of Zeste Polycomb group proteins, which are encoded by a small gene family in Arabidopsis thaliana, participate to the control of plant development. In the tomato (Solanum lycopersicum), these proteins are encoded by three genes (SlEZ1, SlEZ2 and SlEZ3) that display specific expression profiles. Using a gene specific RNAi strategy, we demonstrate that repression of SlEZ2 correlates with a general reduction of H3K27me3 levels, indicating that SlEZ2 is part of an active PRC2 complex. Reduction of SlEZ2 gene expression impacts the vegetative development of tomato plants, consistent with SlEZ2 having retained at least some of the functions of the Arabidopsis CURLY LEAF (CLF) protein. Notwithstanding, we observed significant differences between transgenic SlEZ2 RNAi tomato plants and Arabidopsis clf mutants. First, we found that reduced SlEZ2 expression has dramatic effects on tomato fruit development and ripening, functions not described in Arabidopsis for the CLF protein. In addition, repression of SlEZ2 has no significant effect on the flowering time or the control of flower organ identity, in contrast to the Arabidopsis clf mutation. Taken together, our results are consistent with a diversification of the function of CLF orthologues in plants, and indicate that although partly conserved amongst plants, the function of EZ proteins need to be newly investigated for non-model plants because they might have been recruited to specific developmental processes.
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Affiliation(s)
- L Boureau
- UMR BFP, University of Bordeaux, 71 Avenue E Bourlaux, 33882, Villenave d'Ornon, France
- Laboratory of Hematology, Centre Hospitalier Universitaire de Bordeaux - Hopital Haut Leveque, 5 Avenue Magellan, 33600, Pessac, France
| | - A How-Kit
- Laboratory for Functional Genomics, Foundation Jean Dausset - CEPH, 75010, Paris, France
| | - E Teyssier
- UMR BFP, University of Bordeaux, 71 Avenue E Bourlaux, 33882, Villenave d'Ornon, France
- Grape Ecophysiology and Functional Biology Laboratory, ISVV, University of Bordeaux, 210 Chemin de Leysotte, CS50008, 33882, Villenave d'Ornon Cédex, France
| | - S Drevensek
- Environmental and Evolutionary Genomics Section, Institut de Biologie de l'Ecole Normale Supérieure CNRS UMR 8197INSERM U1024, 46 rue d'Ulm, 75005, Paris, France
- Institute of Plant Sciences Paris-Saclay, INRA, CNRS, Université, Paris-Sud, Université d'Evry, Université Paris-Diderot, Bâtiment 630, 91405, Orsay, France
| | - M Rainieri
- Environmental and Evolutionary Genomics Section, Institut de Biologie de l'Ecole Normale Supérieure CNRS UMR 8197INSERM U1024, 46 rue d'Ulm, 75005, Paris, France
| | - J Joubès
- Laboratoire de Biogenèse Membranaire, UMR 5200, CNRS, Université de Bordeaux, Bâtiment A3, INRA, 71 Avenue Edouard Bourlaux, 33140, Villenave d'Ornon, France
- Laboratoire de Biogenèse Membranaire, UMR5200, CNRS, Bâtiment A3, INRA, 71 Avenue Edouard Bourlaux, 33140, Villenave d'Ornon, France
| | - L Stammitti
- UMR BFP, University of Bordeaux, 71 Avenue E Bourlaux, 33882, Villenave d'Ornon, France
- Grape Ecophysiology and Functional Biology Laboratory, ISVV, University of Bordeaux, 210 Chemin de Leysotte, CS50008, 33882, Villenave d'Ornon Cédex, France
| | - A Pribat
- UMR BFP, University of Bordeaux, 71 Avenue E Bourlaux, 33882, Villenave d'Ornon, France
| | - C Bowler
- Environmental and Evolutionary Genomics Section, Institut de Biologie de l'Ecole Normale Supérieure CNRS UMR 8197INSERM U1024, 46 rue d'Ulm, 75005, Paris, France
| | - Y Hong
- Research Centre for Plant RNA Signaling, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, People's Republic of China.
- Warwick-Hangzhou RNA Signaling Joint Laboratory, School of Life Sciences, University of Warwick, Warwick, CV4 7AL, UK.
| | - P Gallusci
- UMR BFP, University of Bordeaux, 71 Avenue E Bourlaux, 33882, Villenave d'Ornon, France.
- Grape Ecophysiology and Functional Biology Laboratory, ISVV, University of Bordeaux, 210 Chemin de Leysotte, CS50008, 33882, Villenave d'Ornon Cédex, France.
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Skinner A, Khan SJ, Smith-Bolton RK. Trithorax regulates systemic signaling during Drosophila imaginal disc regeneration. Development 2016; 142:3500-11. [PMID: 26487779 DOI: 10.1242/dev.122564] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Although tissue regeneration has been studied in a variety of organisms, from Hydra to humans, many of the genes that regulate the ability of each animal to regenerate remain unknown. The larval imaginal discs of the genetically tractable model organism Drosophila melanogaster have complex patterning, well-characterized development and a high regenerative capacity, and are thus an excellent model system for studying mechanisms that regulate regeneration. To identify genes that are important for wound healing and tissue repair, we have carried out a genetic screen for mutations that impair regeneration in the wing imaginal disc. Through this screen we identified the chromatin-modification gene trithorax as a key regeneration gene. Here we show that animals heterozygous for trithorax are unable to maintain activation of a developmental checkpoint that allows regeneration to occur. This defect is likely to be caused by abnormally high expression of puckered, a negative regulator of Jun N-terminal kinase (JNK) signaling, at the wound site. Insufficient JNK signaling leads to insufficient expression of an insulin-like peptide, dILP8, which is required for the developmental checkpoint. Thus, trithorax regulates regeneration signaling and capacity.
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Affiliation(s)
- Andrea Skinner
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61853, USA
| | - Sumbul Jawed Khan
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61853, USA
| | - Rachel K Smith-Bolton
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61853, USA
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Ghasemi M, Pawar H, Mishra RK, Brahmachari V. The functional diversity of Drosophila Ino80 in development. Mech Dev 2015; 138 Pt 2:113-121. [PMID: 26253267 DOI: 10.1016/j.mod.2015.07.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 07/28/2015] [Accepted: 07/30/2015] [Indexed: 10/23/2022]
Abstract
Ino80 is well known as a chromatin remodeling protein with the catalytic function of DNA dependent ATPase and is highly conserved across phyla. Ino80 in human and Drosophila is known to form the Ino80 complex in association with the DNA binding protein Ying-Yang 1 (YY1)/Pleiohomeotic (Pho) the Drosophila homologue. We have earlier reported that Ino80 sub-family of proteins has two functional domains, namely, the DNA dependent ATPase and the DNA binding domain. In the background of the essential role of dIno80 in development, we provide evidence of Pho independent function of dIno80 in development and analyze the dual role of dIno80 in activation as well as repression in the context of the homeotic gene Scr (sex combs reduced) in imaginal discs. This differential effect of dIno80 in different imaginal discs suggests the contextual function of dIno80 as an Enhancer of Trithorax and Polycomb (ETP). We speculate on the role of dIno80 as a chromatin remodeler on one hand and a potential recruiter of epigenetic regulatory complexes on the other.
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Affiliation(s)
- Mohsen Ghasemi
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India
| | - Hema Pawar
- Indian Agricultural Research Institute, New Delhi 110012, India
| | - Rakesh K Mishra
- Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India
| | - Vani Brahmachari
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi 110007, India.
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Tijchon E, van Ingen Schenau D, van Opzeeland F, Tirone F, Hoogerbrugge PM, Van Leeuwen FN, Scheijen B. Targeted Deletion of Btg1 and Btg2 Results in Homeotic Transformation of the Axial Skeleton. PLoS One 2015. [PMID: 26218146 PMCID: PMC4517811 DOI: 10.1371/journal.pone.0131481] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Btg1 and Btg2 encode highly homologous proteins that are broadly expressed in different cell lineages, and have been implicated in different types of cancer. Btg1 and Btg2 have been shown to modulate the function of different transcriptional regulators, including Hox and Smad transcription factors. In this study, we examined the in vivo role of the mouse Btg1 and Btg2 genes in specifying the regional identity of the axial skeleton. Therefore, we examined the phenotype of Btg1 and Btg2 single knockout mice, as well as novel generated Btg1-/-;Btg2-/- double knockout mice, which were viable, but displayed a non-mendelian inheritance and smaller litter size. We observed both unique and overlapping phenotypes reminiscent of homeotic transformation along the anterior-posterior axis in the single and combined Btg1 and Btg2 knockout animals. Both Btg1-/- and Btg2-/- mice displayed partial posterior transformation of the seventh cervical vertebra, which was more pronounced in Btg1-/-;Btg2-/- mice, demonstrating that Btg1 and Btg2 act in synergy. Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra. Moreover, Btg2-/- animals displayed complete posterior transformation of the sixth lumbar vertebra to the first sacral vertebra, which was only partially present at a low frequency in Btg1-/- mice. The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation. Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.
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Affiliation(s)
- Esther Tijchon
- Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, The Netherlands
| | | | - Fred van Opzeeland
- Laboratory of Pediatric Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands
| | - Felice Tirone
- Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia 00143, Rome, Italy
| | | | - Frank N. Van Leeuwen
- Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, The Netherlands
| | - Blanca Scheijen
- Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, The Netherlands
- * E-mail:
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Dupont CA, Dardalhon-Cuménal D, Kyba M, Brock HW, Randsholt NB, Peronnet F. Drosophila Cyclin G and epigenetic maintenance of gene expression during development. Epigenetics Chromatin 2015; 8:18. [PMID: 25995770 PMCID: PMC4438588 DOI: 10.1186/s13072-015-0008-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 04/01/2015] [Indexed: 12/31/2022] Open
Abstract
Background Cyclins and cyclin-dependent kinases (CDKs) are essential for cell cycle regulation and are functionally associated with proteins involved in epigenetic maintenance of transcriptional patterns in various developmental or cellular contexts. Epigenetic maintenance of transcription patterns, notably of Hox genes, requires the conserved Polycomb-group (PcG), Trithorax-group (TrxG), and Enhancer of Trithorax and Polycomb (ETP) proteins, particularly well studied in Drosophila. These proteins form large multimeric complexes that bind chromatin and appose or recognize histone post-translational modifications. PcG genes act as repressors, counteracted by trxG genes that maintain gene activation, while ETPs interact with both, behaving alternatively as repressors or activators. Drosophila Cyclin G negatively regulates cell growth and cell cycle progression, binds and co-localizes with the ETP Corto on chromatin, and participates with Corto in Abdominal-B Hox gene regulation. Here, we address further implications of Cyclin G in epigenetic maintenance of gene expression. Results We show that Cyclin G physically interacts and extensively co-localizes on chromatin with the conserved ETP Additional sex combs (ASX), belonging to the repressive PR-DUB complex that participates in H2A deubiquitination and Hox gene silencing. Furthermore, Cyclin G mainly co-localizes with RNA polymerase II phosphorylated on serine 2 that is specific to productive transcription. CycG interacts with Asx, PcG, and trxG genes in Hox gene maintenance, and behaves as a PcG gene. These interactions correlate with modified ectopic Hox protein domains in imaginal discs, consistent with a role for Cyclin G in PcG-mediated Hox gene repression. Conclusions We show here that Drosophila CycG is a Polycomb-group gene enhancer, acting in epigenetic maintenance of the Hox genes Sex combs reduced (Scr) and Ultrabithorax (Ubx). However, our data suggest that Cyclin G acts alternatively as a transcriptional activator or repressor depending on the developmental stage, the tissue or the target gene. Interestingly, since Cyclin G interacts with several CDKs, Cyclin G binding to the ETPs ASX or Corto suggests that their activity could depend on Cyclin G-mediated phosphorylation. We discuss whether Cyclin G fine-tunes transcription by controlling H2A ubiquitination and transcriptional elongation via interaction with the ASX subunit of PR-DUB. Electronic supplementary material The online version of this article (doi:10.1186/s13072-015-0008-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Camille A Dupont
- Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France ; CNRS, IBPS, UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France
| | - Delphine Dardalhon-Cuménal
- Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France ; CNRS, IBPS, UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France
| | - Michael Kyba
- Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455 USA
| | - Hugh W Brock
- Department of Zoology, University of British Columbia, 6270 University Boulevard, V6T 1Z4 Vancouver, BC Canada
| | - Neel B Randsholt
- Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France ; CNRS, IBPS, UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France
| | - Frédérique Peronnet
- Sorbonne Universités, UPMC Univ Paris 06, Institut de Biologie Paris-Seine (IBPS), UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France ; CNRS, IBPS, UMR 7622, Developmental Biology, 9, quai Saint-Bernard, F-75005 Paris, France
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Matsuoka Y, Bando T, Watanabe T, Ishimaru Y, Noji S, Popadić A, Mito T. Short germ insects utilize both the ancestral and derived mode of Polycomb group-mediated epigenetic silencing of Hox genes. Biol Open 2015; 4:702-9. [PMID: 25948756 PMCID: PMC4467190 DOI: 10.1242/bio.201411064] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
In insect species that undergo long germ segmentation, such as Drosophila, all segments are specified simultaneously at the early blastoderm stage. As embryogenesis progresses, the expression boundaries of Hox genes are established by repression of gap genes, which is subsequently replaced by Polycomb group (PcG) silencing. At present, however, it is not known whether patterning occurs this way in a more ancestral (short germ) mode of embryogenesis, where segments are added gradually during posterior elongation. In this study, two members of the PcG family, Enhancer of zeste (E(z)) and Suppressor of zeste 12 (Su(z)12), were analyzed in the short germ cricket, Gryllus bimaculatus. Results suggest that although stepwise negative regulation by gap and PcG genes is present in anterior members of the Hox cluster, it does not account for regulation of two posterior Hox genes, abdominal-A (abd-A) and Abdominal-B (Abd-B). Instead, abd-A and Abd-B are predominantly regulated by PcG genes, which is the mode present in vertebrates. These findings suggest that an intriguing transition of the PcG-mediated silencing of Hox genes may have occurred during animal evolution. The ancestral bilaterian state may have resembled the current vertebrate mode of regulation, where PcG-mediated silencing of Hox genes occurs before their expression is initiated and is responsible for the establishment of individual expression domains. Then, during insect evolution, the repression by transcription factors may have been acquired in anterior Hox genes of short germ insects, while PcG silencing was maintained in posterior Hox genes.
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Affiliation(s)
- Yuji Matsuoka
- Department of Life Systems, Institute of Technology and Science, The University of Tokushima Graduate School, 2-1 Minami-Jyosanjima-cho, Tokushima City, Tokushima 770-8506, Japan
| | - Tetsuya Bando
- Department of Life Systems, Institute of Technology and Science, The University of Tokushima Graduate School, 2-1 Minami-Jyosanjima-cho, Tokushima City, Tokushima 770-8506, Japan Present address: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama city, Okayama, 700-8530, Japan
| | - Takahito Watanabe
- Center for Collaboration among Agriculture, Industry and Commerce, The University of Tokushima, 2-24 Shinkura-cho, Tokushima City, Tokushima 770-8501, Japan
| | - Yoshiyasu Ishimaru
- Department of Life Systems, Institute of Technology and Science, The University of Tokushima Graduate School, 2-1 Minami-Jyosanjima-cho, Tokushima City, Tokushima 770-8506, Japan
| | - Sumihare Noji
- Center for Collaboration among Agriculture, Industry and Commerce, The University of Tokushima, 2-24 Shinkura-cho, Tokushima City, Tokushima 770-8501, Japan
| | - Aleksandar Popadić
- Biological Sciences Department, Wayne State University, Detroit, MI 48202, USA
| | - Taro Mito
- Department of Life Systems, Institute of Technology and Science, The University of Tokushima Graduate School, 2-1 Minami-Jyosanjima-cho, Tokushima City, Tokushima 770-8506, Japan
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36
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di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, Lo-Coco F, Ascenzi P, Nervi C. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol Aspects Med 2015; 41:1-115. [PMID: 25543955 DOI: 10.1016/j.mam.2014.12.003] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 12/15/2014] [Indexed: 02/07/2023]
Abstract
Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.
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Affiliation(s)
- Alessandra di Masi
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy
| | - Loris Leboffe
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Roma I-00146, Italy
| | - Elisabetta De Marinis
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100
| | - Francesca Pagano
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100
| | - Laura Cicconi
- Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy
| | - Cécile Rochette-Egly
- Department of Functional Genomics and Cancer, IGBMC, CNRS UMR 7104 - Inserm U 964, University of Strasbourg, 1 rue Laurent Fries, BP10142, Illkirch Cedex F-67404, France.
| | - Francesco Lo-Coco
- Department of Biomedicine and Prevention, University of Roma "Tor Vergata", Via Montpellier 1, Roma I-00133, Italy; Laboratory of Neuro-Oncohematology, Santa Lucia Foundation, Via Ardeatina, 306, Roma I-00142, Italy.
| | - Paolo Ascenzi
- Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, Roma I-00146, Italy.
| | - Clara Nervi
- Department of Medical and Surgical Sciences and Biotechnologies, University of Roma "La Sapienza", Corso della Repubblica 79, Latina I-04100.
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Engelhorn J, Blanvillain R, Carles CC. Gene activation and cell fate control in plants: a chromatin perspective. Cell Mol Life Sci 2014; 71:3119-37. [PMID: 24714879 PMCID: PMC11113918 DOI: 10.1007/s00018-014-1609-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 03/10/2014] [Accepted: 03/12/2014] [Indexed: 01/02/2023]
Abstract
In plants, environment-adaptable organogenesis extends throughout the lifespan, and iterative development requires repetitive rounds of activation and repression of several sets of genes. Eukaryotic genome compaction into chromatin forms a physical barrier for transcription; therefore, induction of gene expression requires alteration in chromatin structure. One of the present great challenges in molecular and developmental biology is to understand how chromatin is brought from a repressive to permissive state on specific loci and in a very specific cluster of cells, as well as how this state is further maintained and propagated through time and cell division in a cell lineage. In this review, we report recent discoveries implementing our knowledge on chromatin dynamics that modulate developmental gene expression. We also discuss how new data sets highlight plant specificities, likely reflecting requirement for a highly dynamic chromatin.
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Affiliation(s)
- Julia Engelhorn
- Université Grenoble Alpes, UMR5168, 38041, Grenoble, France,
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38
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Tung PY, Knoepfler PS. Epigenetic mechanisms of tumorigenicity manifesting in stem cells. Oncogene 2014; 34:2288-96. [PMID: 24931168 PMCID: PMC4268091 DOI: 10.1038/onc.2014.172] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 05/08/2014] [Accepted: 05/09/2014] [Indexed: 01/04/2023]
Abstract
One of the biggest roadblocks to using stem cells as the basis for regenerative medicine therapies is the tumorigenicity of stem cells. Unfortunately, the unique abilities of stem cells to self-renew and differentiate into a variety of cell types are also mechanistically linked to their tumorigenic behaviors. Understanding the mechanisms underlying the close relationship between stem cells and cancer cells has therefore become a primary goal in the field. In addition, knowledge gained from investigating the striking parallels between mechanisms orchestrating normal embryogenesis and those that invoke tumorigenesis may well serve as the foundation for developing novel cancer treatments. Emerging discoveries have demonstrated that epigenetic regulatory machinery plays important roles in normal stem cell functions, cancer development, and cancer stem cell identity. These studies provide valuable insights into both the shared and distinct mechanisms by which pluripotency and oncogenicity are established and regulated. In this review, the cancer-related epigenetic mechanisms found in pluripotent stem cells and cancer stem cells will be discussed, focusing on both the similarities and the differences.
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Affiliation(s)
- P-Y Tung
- 1] Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, CA, USA [2] UC Davis Genome Center, University of California Davis, Davis, CA, USA [3] UC Davis Comprehensive Cancer Center, Sacramento, CA, USA [4] Institute of Pediatric Regenerative Medicine, Shriners Hospital For Children Northern California, Sacramento, CA, USA
| | - P S Knoepfler
- 1] Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, CA, USA [2] UC Davis Genome Center, University of California Davis, Davis, CA, USA [3] UC Davis Comprehensive Cancer Center, Sacramento, CA, USA [4] Institute of Pediatric Regenerative Medicine, Shriners Hospital For Children Northern California, Sacramento, CA, USA
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39
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Identification of Regulators of the Three-Dimensional Polycomb Organization by a Microscopy-Based Genome-wide RNAi Screen. Mol Cell 2014; 54:485-99. [DOI: 10.1016/j.molcel.2014.03.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 02/11/2014] [Accepted: 02/24/2014] [Indexed: 11/17/2022]
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40
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Orsi GA, Kasinathan S, Hughes KT, Saminadin-Peter S, Henikoff S, Ahmad K. High-resolution mapping defines the cooperative architecture of Polycomb response elements. Genome Res 2014; 24:809-20. [PMID: 24668908 PMCID: PMC4009610 DOI: 10.1101/gr.163642.113] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Polycomb-mediated chromatin repression modulates gene expression during development in metazoans. Binding of multiple sequence-specific factors at discrete Polycomb response elements (PREs) is thought to recruit repressive complexes that spread across an extended chromatin domain. To dissect the structure of PREs, we applied high-resolution mapping of nonhistone chromatin proteins in native chromatin of Drosophila cells. Analysis of occupied sites reveal interactions between transcription factors that stabilize Polycomb anchoring to DNA, and implicate the general transcription factor ADF1 as a novel PRE component. By comparing two Drosophila cell lines with differential chromatin states, we provide evidence that repression is accomplished by enhanced Polycomb recruitment both to PREs and to target promoters of repressed genes. These results suggest that the stability of multifactor complexes at promoters and regulatory elements is a crucial aspect of developmentally regulated gene expression.
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Affiliation(s)
- Guillermo A Orsi
- Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
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41
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Identification of a population of epidermal squamous cell carcinoma cells with enhanced potential for tumor formation. PLoS One 2013; 8:e84324. [PMID: 24376802 PMCID: PMC3869846 DOI: 10.1371/journal.pone.0084324] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 11/17/2013] [Indexed: 01/07/2023] Open
Abstract
Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation.
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42
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Rougeot J, Renard M, Randsholt NB, Peronnet F, Mouchel-Vielh E. The elongin complex antagonizes the chromatin factor Corto for vein versus intervein cell identity in Drosophila wings. PLoS One 2013; 8:e77592. [PMID: 24204884 PMCID: PMC3804554 DOI: 10.1371/journal.pone.0077592] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/10/2013] [Indexed: 01/08/2023] Open
Abstract
Drosophila wings mainly consist of two cell types, vein and intervein cells. Acquisition of either fate depends on specific expression of genes that are controlled by several signaling pathways. The nuclear mechanisms that translate signaling into regulation of gene expression are not completely understood, but they involve chromatin factors from the Trithorax (TrxG) and Enhancers of Trithorax and Polycomb (ETP) families. One of these is the ETP Corto that participates in intervein fate through interaction with the Drosophila EGF Receptor--MAP kinase ERK pathway. Precise mechanisms and molecular targets of Corto in this process are not known. We show here that Corto interacts with the Elongin transcription elongation complex. This complex, that consists of three subunits (Elongin A, B, C), increases RNA polymerase II elongation rate in vitro by suppressing transient pausing. Analysis of phenotypes induced by EloA, B, or C deregulation as well as genetic interactions suggest that the Elongin complex might participate in vein vs intervein specification, and antagonizes corto as well as several TrxG genes in this process. Chromatin immunoprecipitation experiments indicate that Elongin C and Corto bind the vein-promoting gene rhomboid in wing imaginal discs. We propose that Corto and the Elongin complex participate together in vein vs intervein fate, possibly through tissue-specific transcriptional regulation of rhomboid.
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Affiliation(s)
- Julien Rougeot
- Université Pierre et Marie Curie-Paris 6, UMR7622, Paris, France ; Centre National de la Recherche Scientifique, UMR7622, Laboratoire de Biologie du Développement, Paris, France
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43
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Dorighi KM, Tamkun JW. The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila. Development 2013; 140:4182-92. [PMID: 24004944 DOI: 10.1242/dev.095786] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Members of the Polycomb group of repressors and trithorax group of activators maintain heritable states of transcription by modifying nucleosomal histones or remodeling chromatin. Although tremendous progress has been made toward defining the biochemical activities of Polycomb and trithorax group proteins, much remains to be learned about how they interact with each other and the general transcription machinery to maintain on or off states of gene expression. The trithorax group protein Kismet (KIS) is related to the SWI/SNF and CHD families of chromatin remodeling factors. KIS promotes transcription elongation, facilitates the binding of the trithorax group histone methyltransferases ASH1 and TRX to active genes, and counteracts repressive methylation of histone H3 on lysine 27 (H3K27) by Polycomb group proteins. Here, we sought to clarify the mechanism of action of KIS and how it interacts with ASH1 to antagonize H3K27 methylation in Drosophila. We present evidence that KIS promotes transcription elongation and counteracts Polycomb group repression via distinct mechanisms. A chemical inhibitor of transcription elongation, DRB, had no effect on ASH1 recruitment or H3K27 methylation. Conversely, loss of ASH1 function had no effect on transcription elongation. Mutations in kis cause a global reduction in the di- and tri-methylation of histone H3 on lysine 36 (H3K36) - modifications that antagonize H3K27 methylation in vitro. Furthermore, loss of ASH1 significantly decreases H3K36 dimethylation, providing further evidence that ASH1 is an H3K36 dimethylase in vivo. These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation.
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Affiliation(s)
- Kristel M Dorighi
- Department of Molecular Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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44
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Coe BP, Thu KL, Aviel-Ronen S, Vucic EA, Gazdar AF, Lam S, Tsao MS, Lam WL. Genomic deregulation of the E2F/Rb pathway leads to activation of the oncogene EZH2 in small cell lung cancer. PLoS One 2013; 8:e71670. [PMID: 23967231 PMCID: PMC3744458 DOI: 10.1371/journal.pone.0071670] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 07/02/2013] [Indexed: 01/15/2023] Open
Abstract
Small cell lung cancer (SCLC) is a highly aggressive lung neoplasm with extremely poor clinical outcomes and no approved targeted treatments. To elucidate the mechanisms responsible for driving the SCLC phenotype in hopes of revealing novel therapeutic targets, we studied copy number and methylation profiles of SCLC. We found disruption of the E2F/Rb pathway was a prominent feature deregulated in 96% of the SCLC samples investigated and was strongly associated with increased expression of EZH2, an oncogene and core member of the polycomb repressive complex 2 (PRC2). Through its catalytic role in the PRC2 complex, EZH2 normally functions to epigenetically silence genes during development, however, it aberrantly silences genes in human cancers. We provide evidence to support that EZH2 is functionally active in SCLC tumours, exerts pro-tumourigenic functions in vitro, and is associated with aberrant methylation profiles of PRC2 target genes indicative of a “stem-cell like” hypermethylator profile in SCLC tumours. Furthermore, lentiviral-mediated knockdown of EZH2 demonstrated a significant reduction in the growth of SCLC cell lines, suggesting EZH2 has a key role in driving SCLC biology. In conclusion, our data confirm the role of EZH2 as a critical oncogene in SCLC, and lend support to the prioritization of EZH2 as a potential therapeutic target in clinical disease.
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Affiliation(s)
- Bradley P. Coe
- Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada
| | - Kelsie L. Thu
- Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada
- * E-mail:
| | | | - Emily A. Vucic
- Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada
| | - Adi F. Gazdar
- Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Stephen Lam
- Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada
| | - Ming-Sound Tsao
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Department of Pathology, Princess Margaret Hospital University Health Network, Toronto, Canada
| | - Wan L. Lam
- Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada
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45
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Gisselbrecht SS, Barrera LA, Porsch M, Aboukhalil A, Estep PW, Vedenko A, Palagi A, Kim Y, Zhu X, Busser BW, Gamble CE, Iagovitina A, Singhania A, Michelson AM, Bulyk ML. Highly parallel assays of tissue-specific enhancers in whole Drosophila embryos. Nat Methods 2013; 10:774-80. [PMID: 23852450 PMCID: PMC3733245 DOI: 10.1038/nmeth.2558] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 06/03/2013] [Indexed: 01/12/2023]
Abstract
Transcriptional enhancers are a primary mechanism by which tissue-specific gene expression is achieved. Despite the importance of these regulatory elements in development, responses to environmental stresses and disease, testing enhancer activity in animals remains tedious, with a minority of enhancers having been characterized. Here we describe 'enhancer-FACS-seq' (eFS) for highly parallel identification of active, tissue-specific enhancers in Drosophila melanogaster embryos. Analysis of enhancers identified by eFS as being active in mesodermal tissues revealed enriched DNA binding site motifs of known and putative, previously uncharacterized mesodermal transcription factors. Naive Bayes classifiers using transcription factor binding site motifs accurately predicted mesodermal enhancer activity. Application of eFS to other cell types and organisms should accelerate the cataloging of enhancers and understanding how transcriptional regulation is encoded in them.
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Affiliation(s)
- Stephen S Gisselbrecht
- Department of Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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46
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Coradini D, Oriana S. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation. CHINESE JOURNAL OF CANCER 2013; 33:51-67. [PMID: 23845141 PMCID: PMC3935006 DOI: 10.5732/cjc.013.10040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
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Affiliation(s)
- Danila Coradini
- Department of Clinical and Community Health Sciences, Medical Statistics, Biometry and Bioinformatics, University of Milan 20133, Italy.
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47
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Bengani H, Mendiratta S, Maini J, Vasanthi D, Sultana H, Ghasemi M, Ahluwalia J, Ramachandran S, Mishra RK, Brahmachari V. Identification and Validation of a Putative Polycomb Responsive Element in the Human Genome. PLoS One 2013; 8:e67217. [PMID: 23805300 PMCID: PMC3689693 DOI: 10.1371/journal.pone.0067217] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 05/20/2013] [Indexed: 12/31/2022] Open
Abstract
Epigenetic cellular memory mechanisms that involve polycomb and trithorax group of proteins are well conserved across metazoans. The cis-acting elements interacting with these proteins, however, are poorly understood in mammals. In a directed search we identified a potential polycomb responsive element with 25 repeats of YY1 binding motifthatwe designate PRE-PIK3C2B as it occurs in the first intron of human PIK3C2B gene. It down regulates reporter gene expression in HEK cells and the repression is dependent on polycomb group of proteins (PcG). We demonstrate that PRE-PIK3C2B interacts directly with YY1 in vitro and recruits PRC2 complex in vivo. The localization of PcG proteins including YY1 to PRE-PIK3C2B in HEK cells is decreased on knock-down of either YY1 or SUZ12. Endogenous PRE-PIK3C2B shows bivalent marking having H3K27me3 and H3K4me3 for repressed and active state respectively. In transgenic Drosophila, PRE-PIK3C2B down regulates mini-white expression, exhibits variegation and pairing sensitive silencing (PSS), which has not been previously demonstrated for mammalian PRE. Taken together, our results strongly suggest that PRE-PIK3C2B functions as a site of interaction for polycomb proteins.
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Affiliation(s)
- Hemant Bengani
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Shweta Mendiratta
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Jayant Maini
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Dasari Vasanthi
- Centre for Cellular and Molecular Biology (CSIR), Hyderabad, Andhra Pradesh, India
| | - Hina Sultana
- Centre for Cellular and Molecular Biology (CSIR), Hyderabad, Andhra Pradesh, India
| | - Mohsen Ghasemi
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Jasmine Ahluwalia
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Sowmya Ramachandran
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
| | - Rakesh K. Mishra
- Centre for Cellular and Molecular Biology (CSIR), Hyderabad, Andhra Pradesh, India
| | - Vani Brahmachari
- Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India
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48
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Functional and cancer genomics of ASXL family members. Br J Cancer 2013; 109:299-306. [PMID: 23736028 PMCID: PMC3721406 DOI: 10.1038/bjc.2013.281] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 05/08/2013] [Accepted: 05/10/2013] [Indexed: 12/22/2022] Open
Abstract
Additional sex combs-like (ASXL)1, ASXL2 and ASXL3 are human homologues of the Drosophila Asx gene that are involved in the regulation or recruitment of the Polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex. ASXL proteins consist of ASXN, ASXH, ASXM1, ASXM2 and PHD domains. ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor. ASXL family members are epigenetic scaffolding proteins that assemble epigenetic regulators and transcription factors to specific genomic loci with histone modifications. ASXL1 is involved in transcriptional repression through an interaction with PRC2 and also contributes to transcriptional regulation through interactions with BAP1 and/or NHR complexes. Germ-line mutations of human ASXL1 and ASXL3 occur in Bohring-Opitz and related syndromes. Amplification and overexpression of ASXL1 occur in cervical cancer. Truncation mutations of ASXL1 occur in colorectal cancers with microsatellite instability (MSI), malignant myeloid diseases, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, and liver, prostate and breast cancers; those of ASXL2 occur in prostate cancer, pancreatic cancer and breast cancer and those of ASXL3 are observed in melanoma. EPC1-ASXL2 gene fusion occurs in adult T-cell leukaemia/lymphoma. The prognosis of myeloid malignancies with misregulating truncation mutations of ASXL1 is poor. ASXL family members are assumed to be tumour suppressive or oncogenic in a context-dependent manner.
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49
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Golbabapour S, Majid NA, Hassandarvish P, Hajrezaie M, Abdulla MA, Hadi AHA. Gene silencing and Polycomb group proteins: an overview of their structure, mechanisms and phylogenetics. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2013; 17:283-96. [PMID: 23692361 PMCID: PMC3662373 DOI: 10.1089/omi.2012.0105] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
DNA methylation, histone modifications, and chromatin configuration are crucially important in the regulation of gene expression. Among these epigenetic mechanisms, silencing the expression of certain genes depending on developmental stage and tissue specificity is a key repressive system in genome programming. Polycomb (Pc) proteins play roles in gene silencing through different mechanisms. These proteins act in complexes and govern the histone methylation profiles of a large number of genes that regulate various cellular pathways. This review focuses on two main Pc complexes, Pc repressive complexes 1 and 2, and their phylogenetic relationship, structures, and function. The dynamic roles of these complexes in silencing will be discussed herein, with a focus on the recruitment of Pc complexes to target genes and the key factors involved in their recruitment.
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Affiliation(s)
- Shahram Golbabapour
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
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50
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Popkova A, Bernardoni R, Diebold C, Van de Bor V, Schuettengruber B, González I, Busturia A, Cavalli G, Giangrande A. Polycomb controls gliogenesis by regulating the transient expression of the Gcm/Glide fate determinant. PLoS Genet 2012; 8:e1003159. [PMID: 23300465 PMCID: PMC3531469 DOI: 10.1371/journal.pgen.1003159] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 10/26/2012] [Indexed: 11/19/2022] Open
Abstract
The Gcm/Glide transcription factor is transiently expressed and required in the Drosophila nervous system. Threshold Gcm/Glide levels control the glial versus neuronal fate choice, and its perdurance triggers excessive gliogenesis, showing that its tight and dynamic regulation ensures the proper balance between neurons and glia. Here, we present a genetic screen for potential gcm/glide interactors and identify genes encoding chromatin factors of the Trithorax and of the Polycomb groups. These proteins maintain the heritable epigenetic state, among others, of HOX genes throughout development, but their regulatory role on transiently expressed genes remains elusive. Here we show that Polycomb negatively affects Gcm/Glide autoregulation, a positive feedback loop that allows timely accumulation of Gcm/Glide threshold levels. Such temporal fine-tuning of gene expression tightly controls gliogenesis. This work performed at the levels of individual cells reveals an undescribed mode of Polycomb action in the modulation of transiently expressed fate determinants and hence in the acquisition of specific cell identity in the nervous system.
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Affiliation(s)
- Anna Popkova
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UDS, Illkirch, France
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