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Mapping polycomb complexes in human and mouse embryonic stem cells

ABSTRACT: In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes: the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes. Keywords: cell type comparison

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE13084 | GEO | 2008/11/01

SECONDARY ACCESSION(S): PRJNA110911

REPOSITORIES: GEO

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Mapping polycomb complexes in human and mouse embryonic stem cells

Project description:In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes: the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes. Keywords: cell type comparison Suz12, Ezh2, Ring1b ChIP-Seq in singlicate from mouse embryonic stem (mES) cells. H3K4me3, H3K27me3, H3K36me3, Ezh2 and Ring1b ChIP-Seq in singlicate from human embyonic stem cells (hES; H9).

2008-11-01 | E-GEOD-13084 | biostudies-arrayexpress

Deletion of RING1A/B and loss of H2AK119ub1 affects PRC2 occupancy and H3K27me3 genome-wide

Project description:The chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on the prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to the recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. Genetic ablation of catalytic subunit of the PRC1 complex (RINGA/B) and ChIP-seq analysis of PRC1 and PRC2 components confirmed genome-wide decreases in PRC2 occupancy and H3K27me3 levels at PRC target sites. This activity is restricted to variant PRC1 complexes and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for polycomb domain formation and normal development. Together these observations provide a surprising new PRC1-dependent logic for PRC2 occupancy and polycomb domain formation. RING1A-/-;RING1Bfl/fl ES cells were treated with 800M-BM-5M tamoxifen for 48hours and compared to untreated control cells by ChIP-seq for RING1B, SUZ12, EZH2 and H3K27me3.

2014-05-27 | E-GEOD-55697 | biostudies-arrayexpress

Deletion of RING1A/B and loss of H2AK119ub1 affects PRC2 occupancy and H3K27me3 genome-wide

2014-05-27 | GSE55697 | GEO

H3K27me3 ChIP-seq profiling studies of HEK293 cells

Project description:Tri-methylation of histone H3 lysine 27 is catalyzed by Polycomb Repressive Complex 2 (PRC2). By genome-wide mapping of H3K27me3 sites in HEK293 cells, we are able to identify potential sites for PRC1-mediated repression and use these data to inform gene expression experiments in the presence and absence of pharmacological inhibition or KD/KO of various Polycomb subunits.

2019-07-08 | GSE133391 | GEO

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.

2021-09-22 | PXD020684 | Pride

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

2020-08-07 | PXD014290 | Pride

METTL14 Regulates Chromatin Bivalent Domains in Mouse Embryonic Stem Cells [RNA-seq]

Project description:METTL14 (methyltransferase-like 14) is an RNA binding protein that partners with METTL3 to mediate N6-methyladenosine (m6A) methylation of mRNA. Recent studies identified a function for METTL3 in heterochromatin and transcription, but the role of METTL14 in these contexts remains unclear. Here we show that METTL14 binds and regulates mouse embryonic stem cell bivalent domains, which are marked with tri-methylation at lysine 27 of histone H3 (H3K27me3) and tri-methylation at lysine 4 of histone H3 (H3K4me3). Knockout of Mettl14 results in decreased H3K27me3 but increased H3K4me3 levels at bivalent regions, resulting in the resolution of the bivalency and in increased transcription. We demonstrate that bivalent domain regulation by METTL14 is independent of METTL3 or m6A modification. Instead, METTL14 enhances H3K27me3 and reduces H3K4me3 by interacting with and probably recruiting the histone 3 lysine 27 (H3K27) methyltransferase complex PRC2 and the histone 3 lysine 4 (H3K4) demethylases KDM5B to chromatin. Our findings identify a METTL3-independent function of METTL14, important for maintaining the bivalent domains in mESCs, thus revealing a new mechanism of bivalent domain regulation in mammals.

2023-06-19 | GSE206734 | GEO

METTL14 Regulates Chromatin Bivalent Domains in Mouse Embryonic Stem Cells [ChIP-seq]

2023-06-19 | GSE206730 | GEO

H2A ubiquitination is essential for Polycomb Repressive Complex 1-mediated gene regulation in Marchantia polymorpha

Project description:Polycomb repressive complex 1 (PRC1) and PRC2 are chromatin regulators maintaining transcriptional repression by depositing H2A mono-ubiquitination (H2Aub) or H3 lysine 27 tri-methylation (H3K27me3), respectively. While PRC1 is known to be required for transcriptional repression, the contribution of H2Aub in the Polycomb repressive system remains unclear in plants. Here, we directly test the requirement of H2Aub for gene repression in Marchantia polymorpha by generating point mutants in H2A that fail to be ubiquitinated by PRC1. These mutants show reduced H3K27me3 levels on the same target sites as mutants in PRC1 subunits MpBMI1 and the homolog MpBMI1L, revealing that PRC1-catalyzed H2Aub is essential for Polycomb system function. Furthermore, we demonstrate that H2Aub contributes to the PRC1-mediated silencing of genes and transposable elements. Together, our data provide evidence that H2Aub plays indispensable roles in the PRC1-initiated repressive system in Marchantia.

2021-08-13 | GSE164394 | GEO

Variant PRC2.1 and PRC2.2 co-operate to direct H3K27 methylations in ESCs [RNA-seq]

Project description:Polycomb repressive complex 2 (PRC2) is composed of EED, SUZ12, and EZH1/2, and mediates mono-, di- and tri-methylation of Histone H3 at Lysine 27. While, two subcomplexes defined by their specific accessory proteins, termed PRC2.1 (Polycomb-like proteins 1-3, EPOP and PALI1/2) and PRC2.2 (AEBP2 and JARID2) exist, little is known about their differential functions. Here, we show that PRC2.1 and PRC2.2 share the majority of their target genes in mouse embryonic stem cells (ESCs). While loss of all three Polycomb-like proteins (PHF1, MTF2, PHF19) leads to eviction of EPOP and PALI1 from chromatin, PRC2.2 specific components are maintained together with SUZ12 and H3K27me3 at broad Polycomb domains. We show that PRC2.2 localises to PRC1 mediated H2AK119ub1 at these broad Polycomb domains to maintain H3K27me3, even in the absence of PRC2.1. Taken together, these data establish that PRC2.1 and PRC2.2 co-operate to direct H3K27me3, but have independent recruitment mechanisms.

2019-09-11 | GSE127119 | GEO

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