scholarly journals EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Roberta Ragazzini ◽  
Raquel Pérez-Palacios ◽  
Irem H. Baymaz ◽  
Seynabou Diop ◽  
Katia Ancelin ◽  
...  
Keyword(s):  
Polycomb Group ◽  
Initial Number ◽  
Core Complex ◽  
Polycomb Repressive Complex ◽  
Inhibitory Protein ◽  
Polycomb Repressive Complex 2 ◽  
The Core ◽  
Accessory Subunits ◽  
Global Increase ◽  
Late Stages

Abstract The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip−/− might not be fully functional and indicate that fertility is strongly impaired in Ezhip−/− females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes.

scholarly journals EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

2019 ◽  
Author(s):  
R Ragazzini ◽  
R Pérez-Palacios ◽  
HI Baymaz ◽  
S Diop ◽  
K Ancelin ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Critical Role ◽  
Core Complex ◽  
Polycomb Repressive Complex ◽  
Inhibitory Protein ◽  
Polycomb Repressive Complex 2 ◽  
The Core ◽  
Accessory Subunits ◽  
Global Increase ◽  
Late Stages

ABSTRACTThe Polycomb machinery is required for the proper orchestration of gene expression by virtue of its critical role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a new cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion ofEzhipleads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This alteration of the epigenetic content of mature oocytes does not affect the initial number of follicles but is associated with a reduction of follicles in aging mice. We provide evidences that mature oocytesEzhip-/- are not fully functional and that fertility is strongly impaired inEzhip-/- females. Altogether, our study uncovers EZHIP as a novel functional player in the comprehensive chromatin remodeling that occurs in the gonads.

scholarly journals Single-molecule and in silico dissection of the interaction between Polycomb repressive complex 2 and chromatin

2020 ◽  
Vol 117 (48) ◽  
pp. 30465-30475
Author(s):  
Rachel Leicher ◽  
Eva J. Ge ◽  
Xingcheng Lin ◽  
Matthew J. Reynolds ◽  
Wenjun Xie ◽  
...  
Keyword(s):  
Single Molecule ◽  
Polycomb Group ◽  
Chromatin Interaction ◽  
Binding Modes ◽  
Polycomb Repressive Complex ◽  
Single Molecule Force Spectroscopy ◽  
Polycomb Repressive Complex 2 ◽  
Major Interest ◽  
Accessory Subunits ◽  
Dynamics Simulations

Polycomb repressive complex 2 (PRC2) installs and spreads repressive histone methylation marks on eukaryotic chromosomes. Because of the key roles that PRC2 plays in development and disease, how this epigenetic machinery interacts with DNA and nucleosomes is of major interest. Nonetheless, the mechanism by which PRC2 engages with native-like chromatin remains incompletely understood. In this work, we employ single-molecule force spectroscopy and molecular dynamics simulations to dissect the behavior of PRC2 on polynucleosome arrays. Our results reveal an unexpectedly diverse repertoire of PRC2 binding configurations on chromatin. Besides reproducing known binding modes in which PRC2 interacts with bare DNA, mononucleosomes, and adjacent nucleosome pairs, our data also provide direct evidence that PRC2 can bridge pairs of distal nucleosomes. In particular, the “1–3” bridging mode, in which PRC2 engages two nucleosomes separated by one spacer nucleosome, is a preferred low-energy configuration. Moreover, we show that the distribution and stability of different PRC2–chromatin interaction modes are modulated by accessory subunits, oncogenic histone mutations, and the methylation state of chromatin. Overall, these findings have implications for the mechanism by which PRC2 spreads histone modifications and compacts chromatin. The experimental and computational platforms developed here provide a framework for understanding the molecular basis of epigenetic maintenance mediated by Polycomb-group proteins.

scholarly journals Association of BMI1 with Polycomb Bodies Is Dynamic and Requires PRC2/EZH2 and the Maintenance DNA Methyltransferase DNMT1

2005 ◽  
Vol 25 (24) ◽  
pp. 11047-11058 ◽  
Author(s):  
Inmaculada Hernández-Muñoz ◽  
Panthea Taghavi ◽  
Coenraad Kuijl ◽  
Jacques Neefjes ◽  
Maarten van Lohuizen
Keyword(s):  
Dna Methyltransferase ◽  
Pericentric Heterochromatin ◽  
Polycomb Group ◽  
Gene Repression ◽  
Kinetic Properties ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Nuclear Structures ◽  
Stable Maintenance ◽  
Polycomb Bodies

ABSTRACT Polycomb group (PcG) proteins are epigenetic chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized. Polycomb repressive complex 2 (PRC2) is thought to be involved in the initiation of gene silencing, whereas Polycomb repressive complex 1 (PRC1) is implicated in the stable maintenance of gene repression. Here, we investigate the kinetic properties of the binding of one of the PRC1 core components, BMI1, with PcG bodies. PcG bodies are unique nuclear structures located on regions of pericentric heterochromatin, found to be the site of accumulation of PcG complexes in different cell lines. We report the presence of at least two kinetically different pools of BMI1, a highly dynamic and a less dynamic fraction, which may reflect BMI1 pools with different binding capacities to these stable heterochromatin domains. Interestingly, PRC2 members EED and EZH2 appear to be essential for BMI1 recruitment to the PcG bodies. Furthermore, we demonstrate that the maintenance DNA methyltransferase DNMT1 is necessary for proper PcG body assembly independent of DNMT-associated histone deacetylase activity. Together, these results provide new insights in the mechanism for regulation of chromatin silencing by PcG proteins and suggest a highly regulated recruitment of PRC1 to chromatin.

scholarly journals Phylogenetic profiling suggests early origin of the core subunits of Polycomb Repressive Complex 2 (PRC2)

2021 ◽  
Author(s):  
Abdoallah Sharaf ◽  
Mallika Vijayanathan ◽  
Miroslav Obornik ◽  
iva Mozgova
Keyword(s):  
Developmental Regulation ◽  
Structural Diversity ◽  
Polycomb Group ◽  
Catalytic Subunit ◽  
Set Domain ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Domains Of Life ◽  
Domain Protein ◽  
Phylogenetic Profiling

Polycomb Repressive Complex 2 (PRC2) is involved in establishing transcriptionally silent chromatin states through its ability to methylate lysine 27 of histone H3 by the catalytic subunit Enhancer of zeste [E(z)]. Polycomb group (PcG) proteins play a crucial role in the maintenance of cell identity and in developmental regulation. Previously, the diversity of PRC2 subunits within some eukaryotic lineages has been reported and its presence in early eukaryotic evolution has been hypothesized. So far however, systematic survey of the presence of PRC2 subunits in species of all eukaryotic lineages is missing. Here, we report the diversity of PRC2 core subunit proteins in different eukaryotic supergroups with emphasis on the early-diverged lineages and explore the molecular evolution of PRC2 subunits by phylogenetics. In detail, we investigate the SET-domain protein sequences and their evolution across the four domains of life and particularly focus on the structural diversity of the SET-domain subfamily containing E(z), the catalytic subunit of PRC2. We show that PRC2 subunits are already present in early eukaryotic lineages, strengthening the support for PRC2 emergence prior to diversification of eukaryotes. We identify a common presence of E(z) and ESC, suggesting that Su(z)12 may have emerged later and/or may be dispensable from the evolutionarily conserved functional core of PRC2. Furthermore, our results broaden our understanding of the E(z) evolution within the SET-domain protein family, suggesting possibilities of function evolution. Through this, we shed light on a possible emerging point of the PRC2 and the evolution of its function in eukaryotes.

scholarly journals The histone variant H2A.Z is required to establish normal patterns of H3K27 methylation in Neurospora crassa

2020 ◽  
Author(s):  
Abigail J. Courtney ◽  
Masayuki Kamei ◽  
Aileen R. Ferraro ◽  
Kexin Gai ◽  
Qun He ◽  
...  
Keyword(s):  
Neurospora Crassa ◽  
Molecular Mechanisms ◽  
Histone Variant ◽  
Polycomb Group ◽  
Stable Gene ◽  
Polycomb Group Proteins ◽  
Polycomb Repressive Complex ◽  
Facultative Heterochromatin ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation

ABSTRACTNeurospora crassa contains a minimal Polycomb repression system, which provides rich opportunities to explore Polycomb-mediated repression across eukaryotes and enables genetic studies that can be difficult in plant and animal systems. Polycomb Repressive Complex 2 is a multi-subunit complex that deposits mono-, di-, and tri-methyl groups on lysine 27 of histone H3, and tri-methyl H3K27 is a molecular marker of transcriptionally repressed facultative heterochromatin. In mouse embryonic stem cells and multiple plant species, H2A.Z has been found to be co-localized with H3K27 methylation. H2A.Z is required for normal H3K27 methylation in these experimental systems, though the regulatory mechanisms are not well understood. We report here that Neurospora crassa mutants lacking H2A.Z or SWR-1, the ATP-dependent histone variant exchanger, exhibit a striking reduction in levels of H3K27 methylation. RNA-sequencing revealed downregulation of eed, encoding a subunit of PRC2, in an hH2Az mutant compared to wild type and overexpression of EED in a ΔhH2Az;Δeed background restored most H3K27 methylation. Reduced eed expression leads to region-specific losses of H3K27 methylation suggesting that EED-dependent mechanisms are critical for normal H3K27 methylation at certain regions in the genome.AUTHOR SUMMARYEukaryotic DNA is packaged with histone proteins to form a DNA-protein complex called chromatin. Inside the nucleus, chromatin can be assembled into a variety of higher-order structures that profoundly impact gene expression. Polycomb Group proteins are important chromatin regulators that control assembly of a highly condensed form of chromatin. The functions of Polycomb Group proteins are critical for maintaining stable gene repression during development of multicellular organisms, and defects in Polycomb proteins are linked to disease. There is significant interest in elucidating the molecular mechanisms that regulate the activities of Polycomb Group proteins and the assembly of transcriptionally repressed chromatin domains. In this study, we used a model fungus to investigate the regulatory relationship between a histone variant, H2A.Z, and a conserved histone modifying enzyme complex, Polycomb Repressive Complex 2 (PRC2). We found that H2A.Z is required for normal expression of a PRC2 component. Mutants that lack H2A.Z have defects in chromatin structure at some parts of the genome, but not others. Identification of PRC2-target domains that are differentially dependent on EED provides insights into the diverse mechanisms that regulate assembly and maintenance of facultative heterochromatin in a simple model system.Data Reference NumbersGSE146611

scholarly journals Identification of Polycomb Repressive Complex 1 and 2 Core Components in Hexaploid Bread Wheat

2019 ◽  
Author(s):  
Beáta Strejčková ◽  
Radim Čegan ◽  
Ales Pecinka ◽  
Zbyněk Milec ◽  
Jan Šafář
Keyword(s):  
Bread Wheat ◽  
Developmental Stages ◽  
Gene Families ◽  
Polycomb Group ◽  
Transcriptional Analysis ◽  
Histone H2a ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Core Components ◽  
Polycomb Repressive Complex 1

ABSTRACTPolycomb repressive complex 1 and 2 play important roles in epigenetic gene regulation by posttranslationally modifying specific histone residues. Polycomb repressive complex 2 is responsible for the trimethylation of lysine 27 on histone H3, while Polycomb repressive complex 1 catalyzes the monoubiquitination of histone H2A at lysine 119. Although these biochemical functions are evolutionarily conserved, studies in animals and plants, mainly Arabidopsis thaliana, showed that specific subunits have evolved into small gene families, with individual members acting at different developmental stages or responding to specific environmental stimuli. However, the evolution of polycomb group gene families in monocots, particularly those with complex allopolyploid origins, is unknown. Here, we present the in silico identification of the Polycomb repressive complex 1 and 2 subunits in allohexaploid bread wheat, the reconstruction of their evolutionary history and a transcriptional analysis over a series of 33 developmental stages. The identification and chromosomal location of the Polycomb repressive complex 1 and 2 core components in bread wheat may enable a deeper understanding of developmental processes, including vernalization in commonly grown winter wheat.

scholarly journals The Core of the Polycomb Repressive Complex Is Compositionally and Functionally Conserved in Flies and Humans

2002 ◽  
Vol 22 (17) ◽  
pp. 6070-6078 ◽  
Author(s):  
Stuart S. Levine ◽  
Alona Weiss ◽  
Hediye Erdjument-Bromage ◽  
Zhaohui Shao ◽  
Paul Tempst ◽  
...  
Keyword(s):  
Human Cancer ◽  
Polycomb Group ◽  
Gene Repression ◽  
Homeotic Gene ◽  
Homeotic Genes ◽  
Polycomb Repressive Complex ◽  
Developmental Defects ◽  
The Core ◽  
Core Proteins ◽  
And Function

ABSTRACT The Polycomb group (PcG) genes are required to maintain homeotic genes in a silenced state during development in drosophila and mammals and are thought to form several distinct silencing complexes that maintain homeotic gene repression during development. Mutations in the PcG genes result in developmental defects and have been implicated in human cancer. Although some PcG protein domains are conserved between flies and humans, substantial regions of several PcG proteins are divergent and humans contain multiple versions of each PcG gene. To determine the effects of these changes on the composition and function of a PcG complex, we have purified a human Polycomb repressive complex from HeLa cells (hPRC-H) that contains homologues of PcG proteins found in drosophila embryonic PRC1 (dPRC1). hPRC-H was found to have fewer components than dPRC1, retaining the PcG core proteins of dPRC1 but lacking most non-PcG proteins. Preparations of hPRC-H contained either two or three different homologues of most of the core PcG proteins, including a new Ph homologue we have named HPH3. Despite differences in composition, dPRC1 and hPRC-H have similar functions: hPRC-H is able to efficiently block remodeling of nucleosomal arrays through a mechanism that does not block the ability of nucleases to access and cleave the arrays.

scholarly journals Bmi1 – A Path to Targeting Cancer Stem Cells

2017 ◽  
Vol 13 (02) ◽  
pp. 147 ◽  
Author(s):  
David Bakhshinyan ◽  
Ashley A Adile ◽  
Chitra Venugopal ◽  
Sheila K Singh ◽  
◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Translational Regulation ◽  
Tumour Progression ◽  
Metastatic Potential ◽  
Polycomb Group ◽  
Polycomb Repressive Complex ◽  
Self Renewal ◽  
Polycomb Repressive Complex 2 ◽  
Wide Range

The Polycomb group (PcG) genes encode for proteins comprising two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). Although the initial discovery of PcG genes was made in Drosophila, as transcriptional repressors of homeotic (HOX) genes. Polycomb repressive complexes have been since implicated in regulating a wide range of cellular processes, including differentiation and self-renewal in normal and cancer stem cells. Bmi1, a subunit of PRC1, has been long implicated in driving self-renewal, the key property of stem cells. Subsequent studies showing upregulation of Bmi1 in several cancers correlated with increased aggressiveness, radioresistance and metastatic potential, provided rationale for development of targeted therapies against Bmi1. Although Bmi1 activity can be reduced through transcriptional, post-transcriptional and post-translational regulation, to date, the most promising approach has been through small molecule inhibitors targeting Bmi1 activity. The post-translational targeting of Bmi1 in colorectal carcinoma, lung adenocarcinoma, multiple myeloma and medulloblastoma have led to significant reduction of self-renewal capacity of cancer stem cells, leading to slower tumour progression and reduced extent of metastatic spread. Further value of Bmi1 targeting in cancer can be established through trials evaluating the combinatorial effect of Bmi1 inhibition with current ‘gold standard’ therapies.

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