Heritable human Polycomb silencing is locus-dependent and requires H2AK119ub1 self-propagation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209986 | GEO | 2024/05/15
REPOSITORIES: GEO
Similar Datasets
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.
2021-01-31 | GSE153496 | GEO
Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in multiple cellular and developmental pathways. However, its molecular network remains poorly defined. We combined quantitative proteomics, transcriptomics and epigenomics to define the core USP7 regulome. We found that USP7 forms a regulatory hub, linking processes involved in the packaging, maintenance and expression of the genome. Further analysis revealed that USP7 regulates non-canonical Polycomb repressive complexes 1 (ncPRC1s) but affects neither canonical PRC1s nor PRC2s. By stabilizing key subunits of PRC1.6 and to a lesser extend PRC1.1, USP7 acts as a rheostat that modulates the global level of H2AK119ub11. Unexpectedly, changes in the genomic deposition of H2AK119ub11 are uncoupled from H3K27me3, challenging prevalent models for Polycomb repression. Indeed, a complete loss of PRC1 and H2AK119ub1 has only a highly restricted effect on H3K27me3. Besides defining the organizational principles of the USP7 regulome, our results reveal selective control of H2AK119ub1 dosage that is disconnected from H3K27me3.
2023-03-11 | PXD030707 | Pride
Project description:Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1) and trimethylation of histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains up to the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.
2021-03-15 | GSE158360 | GEO
Project description:Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1) and trimethylation of histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains up to the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.
2021-03-15 | GSE153530 | GEO
Project description:Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1) and trimethylation of histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains up to the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.
2021-03-15 | GSE153529 | GEO
Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.
2022-11-08 | GSE193014 | GEO
Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.
2022-11-08 | GSE193013 | GEO
Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.
2022-11-12 | GSE217658 | GEO
Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.
2022-11-08 | GSE193019 | GEO
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