Identification of a novel role of MTF2 in the regulation of H3K27me3 by PRC2 (ChIP-Seq)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE111146 | GEO | 2018/02/27
REPOSITORIES: GEO
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Project description:We sequenced mRNA from F9 cells after knockdown of EZH2, SUZ12 and EED by shRNA. EZH2, SUZ12 and EED are the core componnets of PRC2 which repress its target genes by H3K27me3.
2018-02-27 | GSE111145 | GEO
Project description:Identification of a novel role of MTF2 in the regulation of H3K27me3 by PRC2
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Project description:Polycomb Repressive Complexes PRC1 and PRC2 play a crucial role in silencing lineage-specific genes during early embryogenesis. To provide new insights in polycomb biology, we profiled the proximal interactome (proxeome) of the catalytic subunits RNF2 (PRC1) and EZH2 (PRC2) in mouse embryonic stem cells (mESCs). This revealed >100 proteins proximal to PRC12 and PRC21, which mainly comprise transcription factors, transcriptional regulators and RNA binding proteins. To investigate the link between PRC2 and NuA4, and therefore the the link between H4ac an H3K27me3, we perturbed PRC2 both chemically and genetically.The effects on the histone PTMs were measured with LC-MS/MS.
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Project description:The Polycomb repressive complex 2 (PRC2) establishes transcriptionally silent chromatin by catalyzing histone H3 lysine 27 trimethylation (H3K27me3). Although cofactors such as MTF2 and JARID2 are known to direct PRC2 to nucleation sites and stimulate its catalytic activity, the role of the PRC2-associated factor EPOP has remained unclear and even controversial. Here, we combine biochemical reconstitution and a cellular EED-rescue system to define EPOP’s contribution to initial PRC2 recruitment and de novo H3K27me3 deposition. We show that EPOP, like MTF2, directly stimulates PRC2 histone methyltransferase activity in vitro. In vivo, EPOP is dispensable for initial PRC2 recruitment but promotes de novo H3K27me3 deposition in cooperation with MTF2 and JARID2. Mechanistically, electrophoretic mobility shift assays and reconstituted chromatin substrates reveal that EPOP and MTF2 enhance PRC2–nucleosome binding in a sequence- and chromatin-dependent manner: EPOP preferentially potentiates activity on GA-rich dinucleosomes, whereas MTF2 favors GCN-rich substrates. Together, these findings position EPOP as a positive regulator of PRC2 function during the establishment of H3K27me3 domains, and reveal a paradigm in which distinct cofactors confer DNA-sequence-specific control of de novo H3K27me3 deposition.
2026-01-09 | GSE306783 | GEO
Project description:Identification of a novel role of MTF2 in the regulation of H3K27me3 by PRC2 (ChIP-Seq)
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Project description:Identification of a novel role of MTF2 in the regulation of H3K27me3 by PRC2 (RNA-Seq)
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Project description:The ground state of pluripotency is defined as a basal proliferative state free of epigenetic restriction, represented by mouse embryonic stem cells (ESCs) cultured with two kinase inhibitors (so-called “2i”). Through comparison with serum-grown ESCs, we identify epigenetic features characterizing 2i ESCs by proteome profiling of chromatin including post-translational histone modifications. The most prominent difference is H3K27me3 and its enzymatic writer complex PRC2 that are highly abundant on eu- and heterochromatin in 2i ESCs, with H3K27me3 redistributing outside canonical PRC2 targets in a CpG-dependent fashion. Using PRC2-deficient 2i ESCs, we identify epigenetic crosstalk with H3K27me3, including significant increases in H4 acetylation and DNA methylation. This suggests that the unique H3K27me3 configuration protects 2i ESCs from preparation to lineage priming. Interestingly, removal of DNA methylation in PRC2-deficient 2i ESCs lacking H3K27me3 using 5-azacytidine hardly affected ESC viability and transcriptome, showing that ESCs are independent of both major repressive epigenetic marks.
2018-11-21 | PXD007154 | Pride
Project description:BackgroundThe ability to deposit histone H3K27-trimethyl (me3) marks is essential for transcriptional repression by Polycomb Repressive Complex 2 (PRC2). This is largely attributed to Polycomb repressive complex 1 (PRC1), whose recruitment is H3K27me3-dependent. Yet it is unclear how H3K27me3 contributes to transcription regulation independently of PRC1.ResultsTo address this question, we identified H3K27me3-binding proteins in the unicellular eukaryote Paramecium where PRC2 targets transposable elements (TEs) and PRC1 is absent. We show that the chromodomain protein Firefly is a H3K27me3 reader in vitro and accumulates onto TEs in a H3K27me3-dependent manner. We also identify Firefly interactors: Sleepy, a coiled-coil containing protein and TfIIs4, a transcription elongation factor. We show that Firefly, Sleepy and TfIIs4 are jointly required in vivo for correct H3K27me3 accumulation and nascent transcription at TEs.ConclusionsThis positive feedback loop to enrich H3K27me3 at TEs is analogous to self-reinforcing loops leading to H3K9 methylation at repeats in fungi, plants and animals. Our work reveals a unique association between H3K27me3 readers and active transcription.
2026-03-03 | PXD065449 | Pride
Project description:Polycomb repression of gene expression is critical for development, with a pivotal role for trimethylation of lysine 27 of histone H3 (H3K27me3) deposited by Polycomb Repressive Complex 2 (PRC2). While the function and regulation of PRC2 have been extensively studied, the mechanism(s) by which it is recruited to specific genomic targets has remained largely elusive, in particular in vertebrates. Here we identify the PRC2-associated protein Mtf2 as a novel DNA methylation-sensitive PRC2 recruiter in mouse embryonic stem cells (mESCs). Mtf2 directly binds to DNA and is essential for recruitment of PRC2 both in vitro and in vivo. Genome-wide recruitment of the PRC2 catalytic subunit Ezh2 to genomic targets is drastically impaired in Mtf2 knock-out mESCs, resulting in largely reduced H3K27me3 deposition. Mtf2 selectively binds regions with high density of closely spaced unmethylated CpG-containing motifs with a locally unwound helical structure. This binding is dependent on one of the Mtf2 PHD domains, a protein domain shared among Pcl homologs, and an Mtf2-specific domain. The sequences bound by Mtf2 are enriched in PRC2-repressed CpG island-containing targets in zebrafish, Xenopus, mouse and human, suggesting that Mtf2-mediated PRC2 recruitment to unmethylated genomic regions is conserved among vertebrates.
2018-05-07 | PXD005821 | Pride
Project description:Polycomb repressive complex 2 (PRC2) accessory proteins play substoichiometric, tissue-specific roles to recruit PRC2 to specific genomic loci or increase enzymatic activity, while PRC2 core proteins are required for complex stability and global levels of trimethylation of histone 3 at lysine 27 (H3K27me3). Here, we demonstrate a role for the classical PRC2 accessory protein Mtf2/Pcl2 in the hematopoietic system that is more akin to that of a core PRC2 protein. Mtf2-/- erythroid progenitors demonstrate markedly decreased core PRC2 protein levels and a global loss of H3K27me3 at promoter-proximal regions. The resulting de-repression of transcriptional and signaling networks blocks definitive erythroid development, culminating in Mtf2-/- embryos dying by e15.5 due to severe anemia. Gene regulatory network (GRN) analysis demonstrated Mtf2 directly regulates Wnt signaling in erythroblasts, leading to activated canonical Wnt signaling in Mtf2-deficient erythroblasts, while chemical inhibition of canonical Wnt signaling rescued Mtf2-deficient erythroblast differentiation in vitro. Using a combination of in vitro, in vivo and systems analyses, we demonstrate that Mtf2 is a critical epigenetic regulator of Wnt signaling during erythropoiesis and recast the role of polycomb accessory proteins in a tissue-specific context.
2018-07-26 | GSE72286 | GEO