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H2AK119ub1 counteracts MLL2 functions to direct heritable H3K27me3 formation in mouse oocytes [CATCH-seq and CUT&RUN]

ABSTRACT: Polycomb group (PcG) and Trithorax group (TrxG) family proteins form repressive and permissive states of chromatin, respectively, to regulate developmental genes. They counteract with each other at bivalent chromatin marked by Polycomb repressive complex 2 (PRC2)-deposited H3K27me3, PRC1-deposited H2AK119ub1, and MLL2-deposited H3K4me3. However, it is unknown how they counteract to form bivalent chromatin in mammalian development. Here, by using mouse oocytes as a model in which bivalent chromatin and H3K27me3-dependent noncanonical imprinting are established during the non-dividing growth phase of oogenesis, we show that H3K27me3 is deposited at H3K4me3-premarked promoters in an H2AK119ub1-dependent manner. We find that H2AK119ub1 deficiency causes transcriptional derepression of bivalent genes and H3K36me2/3 deposition across the gene bodies, which are concurrent with loss of H3K27me3 at both promoters and gene bodies in Pcgf1/6 double KO oocytes. Importantly, upon combinatorial deficiency of H2AK119ub1 and promoter H3K4me3, both transcriptional repression and H3K27me3 deposition are substantially restored in Pcgf1/6/Mll2 TKO oocytes. This leads to restoration of maternal allele silencing of Sfmbt2, a noncanonical imprinted gene essential for placental development, and consequently normalization of placental growth in the offspring. Taken together, we propose that vPRC1-mediated H2AK119ub1 antagonizes MLL2 functions to confer intergenerationally heritable H3K27me3 during oogenesis. This study uncovers how PcG and TrxG counteraction shapes the maternal epigenome for the next generation development.

ORGANISM(S): Mus musculus

PROVIDER: GSE292333 | GEO | 2026/04/01

REPOSITORIES: GEO

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H2AK119ub1 counteracts MLL2 functions to direct heritable H3K27me3 formation in mouse oocytes

Project description:Polycomb group (PcG) and Trithorax group (TrxG) family proteins form repressive and permissive states of chromatin, respectively, to regulate developmental genes. They counteract with each other at bivalent chromatin marked by Polycomb repressive complex 2 (PRC2)-deposited H3K27me3, PRC1-deposited H2AK119ub1, and MLL2-deposited H3K4me3. However, it is unknown how they counteract to form bivalent chromatin in mammalian development. Here, by using mouse oocytes as a model in which bivalent chromatin and H3K27me3-dependent noncanonical imprinting are established during the non-dividing growth phase of oogenesis, we show that H3K27me3 is deposited at H3K4me3-premarked promoters in an H2AK119ub1-dependent manner. We find that H2AK119ub1 deficiency causes transcriptional derepression of bivalent genes and H3K36me2/3 deposition across the gene bodies, which are concurrent with loss of H3K27me3 at both promoters and gene bodies in Pcgf1/6 double KO oocytes. Importantly, upon combinatorial deficiency of H2AK119ub1 and promoter H3K4me3, both transcriptional repression and H3K27me3 deposition are substantially restored in Pcgf1/6/Mll2 TKO oocytes. This leads to restoration of maternal allele silencing of Sfmbt2, a noncanonical imprinted gene essential for placental development, and consequently normalization of placental growth in the offspring. Taken together, we propose that vPRC1-mediated H2AK119ub1 antagonizes MLL2 functions to confer intergenerationally heritable H3K27me3 during oogenesis. This study uncovers how PcG and TrxG counteraction shapes the maternal epigenome for the next generation development.

2026-04-01 | GSE292237 | GEO

CpG Island Structure and Trithorax/Polycomb Chromatin Domains in Human Cells

Project description:TrxG and PcG complexes play key roles in the epigenetic regulation of development through H3K4me3 and H3K27me3 modification at specific sites throughout the human genome, but how these sites are selected is poorly understood. We find that in pluripotent cells, clustered CpG islands at genes predict occupancy of H3K4me3 and H3K27me3, and these "bivalent" chromatin domains precisely span the boundaries of CpG island clusters. Examination of two histone modifications (H3K4me3 and H3K27me3) in human induced pluripotent stem (hiPS) M23F cells.

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Project description:Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalently marked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking at bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation. ChIP-Seq in mouse embryonic stem (mES) cells for MLL2. ChIP-seq of H3K4me1, H3K4me3 and H3K27me3 for mES cells with RNAi against MLL2(shMLL2) and control (shGFP). ChIP-seq of H3K4me3 in mES cells with RNAi against MLL3 (shMLL3). RNA-seq of mES cells with RNAi against MLL2 and control (shGFP). RNA-seq of control mES cells (shGFP) or MLL2 RNAi mES cells (shMLL2) induced with RA for 6h and 12h.

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Mll2 is required for H3K4 trimethylation on bivalent promoters in ES cells whereas Mll1 is redundant

Project description:Trimethylation of histone 3 lysine 4 (H3K4me3) at promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax-Group action. Here we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. In contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed indicating functional back-up between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naM-CM-/ve epigenome and Polycomb-Group action on bivalent promoters blocks premature establishment of active, Set1C bound, promoters. ChIP-Seq to study MLL2 function using H3K4me3 (12 samples), H3K27me3 (4 samples), Pol2 (1 sample) or GFP (7 samples) antibody, and 6 RNA-Seq profiles

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Bivalent complexes of PRC1 with orthologs of BRD4 and MOZ/MORF target developmental genes in Drosophila

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MLL2 conveys transcription-independent H3K4me3 in the oocyte

Project description:Trimethylation of histone 3 lysine 4 (H3K4me3) is classically thought of as a mark of active promoters and yet it occurs at untranscribed domains. Partial redundancy of H3K4 methyltransferases has made it difficult to delineate the mechanisms underlying genomic targeting of H3K4me3. The oocyte provides an attractive system to investigate this, because extensive acquisition of H3K4me3 occurs in a non-dividing cell and ablation of a single H3K4 methyltransferase, Mll2, prevents most H3K4me3. We developed low-input chromatin immunoprecipitation to interrogate promoter associated histone modifications H3K4me3, H3K27ac and H3K27me3 throughout oogenesis. In non-growing oocytes, H3K4me3 was restricted to transcriptionally active promoters, but as oogenesis progresses, H3K4me3 accumulates in a transcription-independent manner: targeted to broad inter-genic regions, putative enhancers, and transcriptionally silent H3K27me3-marked promoters. Consequently, thousands of bivalent domains are established during oogenesis. Ablation of Mll2 resulted in loss of transcription-independent H3K4me3, with limited effects on transcription-coupled H3K4me3 or gene expression. Deletion of Dnmt3a/b showed that DNA methylation protects regions from acquiring H3K4me3. Our findings show that there are two independent mechanisms of targeting H3K4me3 to genomic elements, with MLL2 recruited to unmethylated CpG-rich regions independently of transcription.

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H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos

Project description:Parental epigenomes are established during gametogenesis. While they are largely reset soon after fertilization in mammals, maternal histone H3 tri-methylation at lysine 27 (H3K27me3) is inherited by the next generation embryos. How H3K27me3 is properly established in oocytes and passed on to the embryos remains elusive. Furthermore, although polycomb repressive complex 2 (PRC2)-mediated H3K27me3 is known to interplay with PRC1-mediated mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1) to coordinate repressive polycomb domains in embryonic stem cells (ESCs), how they act in vivo remains unknown. To address these questions, here we profiled H2AK119ub1 dynamics during mouse oogenesis and preimplantation development, and investigated its functions in maternal inheritance of H3K27me3. Integrative analyses with H3K27me3 dynamics revealed that an unusually broad and distal-rich distribution of H2AK119ub1 is established during oogenesis and co-transmitted to embryos together with H3K27me3. On the other hand, an ESC-like canonical distribution of H2AK119ub1 is newly established at the 2-cell stage, a few days earlier than that of H3K27me3. Deficiency in polycomb group ring finger 1 (PCGF1) and PCGF6, essential components of variant PRC1 (vPRC1), leads to massive reduction of H2AK119ub1 and gene-selective loss of H3K27me3 in oocytes. The gene-selective deficient state of H3K27me3 is irreversibly inherited by embryos, which causes bi-allelic expression of H3K27me3-dependent imprinted genes, including Xist, embryonic sublethality, and placental enlargement at term. Collectively, our study not only revealed instructive in vivo dynamics of H2AK119ub1 for H3K27me3 establishment at the maternal-to-embryonic transition, but also identified PCGF1/6-PRC1 as an essential player for intergenerational epigenetic inheritance.

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Role of CxxC-finger Protein 1 in the Establishment of Epigenetic Landscapes in Mouse Oocytes

Project description:During oogenesis, oocytes gain competence to accomplish meiotic maturation and prepare for embryonic development following fertilization. Trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1), the chromatin-binding subunit of SETD1 methyltransferase, impairs the H3K4me3 accumulation during murine oogenesis and caused changes in chromatin configurations. This study investigated the changes of genomic H3K4me3 landscapes in oocytes after Cxxc1 knockout, as well as the influences of H3K4me3 changes on other epigenetic marks including DNA methylation, H3K27me3, H2AK119ub1, and H3K36me3. Chromatin immunoprecipitation and sequencing results indicated that H3K4me3 is globally decreased after abolishing Cxxc1, including both the promoter region and the gene body. The results also demonstrate that CXXC1 and another histone H3 methyltransferase MLL2 have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. In addition, Cxxc1 deletion caused a significant decrease of DNA methylation level in oocytes, and affected H3K27me3 and H2AK119ub1 distributions in the maternal genome, particularly at the regions that have high DNA methylation levels. The changes of epigenetic networks caused by Cxxc1 deletion correlated with transcription changes of the genes in the corresponding genomic regions. Taken together, this study provided mechanistic explanations underlying the phenotypes and molecular defects in Cxxc1 deleted oocytes, and highlighted a role of CXXC1 in orchestrating multiple factors to build up the appropriate epigenetic states of maternal genome during oocyte maturation.

2021-02-04 | GSE159581 | GEO

Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells

2013-08-11 | GSE48172 | GEO