Polycomb Proteins

A special issue of Epigenomes (ISSN 2075-4655).

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 24339

Special Issue Editors


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Guest Editor
Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain
Interests: cancer epigenetics; polycomb; chromatin remodeling; gene silencing; cellular differentiation; RNA modifications
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Guest Editor
1. Sylvester Comprehensive Cancer Center, Biomedical Research Building, 1501 NW 10th Avenue, Miami, FL 33136, USA
2. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Interests: cancer epigenetics; Polycomb; development; chromatin architecture; breast cancer

Special Issue Information

Dear Colleagues,

Polycomb (PcG) and trithorax (TrxG) groups of proteins are highly conserved multiprotein complexes involved in many biological functions, such as embryonic development, cell proliferation, cell identity, and cell-fate choices. Mechanistically, these chromatin-modifying complexes act antagonistically with respect to gene regulation. The deregulation of proteins belonging to PcG or TrxG families, or alterations in the subunit composition of these complexes, leads to a wide spectrum of developmental disorders and diseases, including cancer.

This Special Issue is focused on the function of PcG and TrxG complexes, both in development and disease. We will consider reviews, research articles, or methods manuscripts of exceptional interest on the following topics:

  • Role of PcG or TrxG proteins in cell identity and cell-fate choices;
  • Role of PcG or TrxG proteins in development and disease;
  • Role of PcG or TrxG in gene expression and three-dimensional organization of the genome.

Prof. Dr. Luciano Di Croce
Prof. Dr. Lluis Morey
Guest Editors

Manuscript Submission Information

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Keywords

  • polycomb
  • trithorax
  • chromatin modifying complex
  • gene expression
  • epigenetics

Published Papers (5 papers)

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Research

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24 pages, 4419 KiB  
Article
Regulation of Polyhomeotic Condensates by Intrinsically Disordered Sequences That Affect Chromatin Binding
by Ibani Kapur, Elodie L. Boulier and Nicole J. Francis
Epigenomes 2022, 6(4), 40; https://doi.org/10.3390/epigenomes6040040 - 3 Nov 2022
Cited by 4 | Viewed by 2788
Abstract
The Polycomb group (PcG) complex PRC1 localizes in the nucleus in condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains an oligomerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian [...] Read more.
The Polycomb group (PcG) complex PRC1 localizes in the nucleus in condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains an oligomerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian cells. A truncated version of Ph containing the SAM (mini-Ph) forms phase-separated condensates with DNA or chromatin in vitro, suggesting that PcG bodies may form through SAM-driven phase separation. In cells, Ph forms multiple small condensates, while mini-Ph typically forms a single large nuclear condensate. We therefore hypothesized that sequences outside of mini-Ph, which are predicted to be intrinsically disordered, are required for proper condensate formation. We identified three distinct low-complexity regions in Ph based on sequence composition. We systematically tested the role of each of these sequences in Ph condensates using live imaging of transfected Drosophila S2 cells. Each sequence uniquely affected Ph SAM-dependent condensate size, number, and morphology, but the most dramatic effects occurred when the central, glutamine-rich intrinsically disordered region (IDR) was removed, which resulted in large Ph condensates. Like mini-Ph condensates, condensates lacking the glutamine-rich IDR excluded chromatin. Chromatin fractionation experiments indicated that the removal of the glutamine-rich IDR reduced chromatin binding and that the removal of either of the other IDRs increased chromatin binding. Our data suggest that all three IDRs, and functional interactions among them, regulate Ph condensate size and number. Our results can be explained by a model in which tight chromatin binding by Ph IDRs antagonizes Ph SAM-driven phase separation. Our observations highlight the complexity of regulation of biological condensates housed in single proteins. Full article
(This article belongs to the Special Issue Polycomb Proteins)
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Review

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24 pages, 1775 KiB  
Review
RINGs, DUBs and Abnormal Brain Growth—Histone H2A Ubiquitination in Brain Development and Disease
by Lucy Anne Doyle, Firuze Unlu Bektas, Eleftheria Chatzantonaki, Charlotte Repton, Alexandra Derrien and Robert Scott Illingworth
Epigenomes 2022, 6(4), 42; https://doi.org/10.3390/epigenomes6040042 - 2 Dec 2022
Cited by 1 | Viewed by 4530
Abstract
During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including [...] Read more.
During mammalian neurodevelopment, signaling pathways converge upon transcription factors (TFs) to establish appropriate gene expression programmes leading to the production of distinct neural and glial cell types. This process is partially regulated by the dynamic modulation of chromatin states by epigenetic systems, including the polycomb group (PcG) family of co-repressors. PcG proteins form multi-subunit assemblies that sub-divide into distinct, yet functionally related families. Polycomb repressive complexes 1 and 2 (PRC1 and 2) modify the chemical properties of chromatin by covalently modifying histone tails via H2A ubiquitination (H2AK119ub1) and H3 methylation, respectively. In contrast to the PRCs, the Polycomb repressive deubiquitinase (PR-DUB) complex removes H2AK119ub1 from chromatin through the action of the C-terminal hydrolase BAP1. Genetic screening has identified several PcG mutations that are causally associated with a range of congenital neuropathologies associated with both localised and/or systemic growth abnormalities. As PRC1 and PR-DUB hold opposing functions to control H2AK119ub1 levels across the genome, it is plausible that such neurodevelopmental disorders arise through a common mechanism. In this review, we will focus on advancements regarding the composition and opposing molecular functions of mammalian PRC1 and PR-DUB, and explore how their dysfunction contributes to the emergence of neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Polycomb Proteins)
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30 pages, 2157 KiB  
Review
Polycomb Directed Cell Fate Decisions in Development and Cancer
by Beatriz German and Leigh Ellis
Epigenomes 2022, 6(3), 28; https://doi.org/10.3390/epigenomes6030028 - 6 Sep 2022
Cited by 8 | Viewed by 6957
Abstract
The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that [...] Read more.
The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers. Full article
(This article belongs to the Special Issue Polycomb Proteins)
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26 pages, 2303 KiB  
Review
De Novo Polycomb Recruitment and Repressive Domain Formation
by Itzel Alejandra Hernández-Romero and Victor Julian Valdes
Epigenomes 2022, 6(3), 25; https://doi.org/10.3390/epigenomes6030025 - 22 Aug 2022
Cited by 4 | Viewed by 3701
Abstract
Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive [...] Read more.
Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive complexes, PRC1 and PRC2, identify their targets and elicit new Polycomb domains during cell differentiation. Classical recruitment models consider the pre-existence of repressive histone marks; still, de novo target binding overcomes the absence of both H3K27me3 and H2AK119ub. The CpG islands (CGIs), non-core proteins, and RNA molecules are involved in Polycomb recruitment. Nonetheless, it is unclear how de novo targets are identified depending on the physiological context and developmental stage and which are the leading players stabilizing Polycomb complexes at domain nucleation sites. Here, we examine the features of de novo sites and the accessory elements bridging its recruitment and discuss the first steps of Polycomb domain formation and transcriptional regulation, comprehended by the experimental reconstruction of the repressive domains through time-resolved genomic analyses in mammals. Full article
(This article belongs to the Special Issue Polycomb Proteins)
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18 pages, 4420 KiB  
Review
The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development
by Chet H. Loh and Gert Jan C. Veenstra
Epigenomes 2022, 6(3), 23; https://doi.org/10.3390/epigenomes6030023 - 12 Aug 2022
Cited by 15 | Viewed by 5158
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Polycomb Proteins)
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