PCGF1-PRC1 safeguards recovery of nucleosome positioning during S-phase to ensure early hematopoiesis
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ABSTRACT:
ORGANISM(S): Mus Musculus (mouse)
SUBMITTER: Haruhiko Koseki
PROVIDER: PXD033883 | JPOST Repository | Sat May 13 00:00:00 BST 2023
REPOSITORIES: jPOST
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Project description:Polycomb repressive complexes 1 and 2 (PRC1 and 2) repress lineage inappropriate genes during development to maintain proper cellular identities. To reveal the function of a variant PRC1 containing PCGF1 (PCGF1-PRC1), we prepared PCGF1 interacting proteins by immunoprecipitation and characterized them by LC-MS/MS.
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Project description:USP7, a ubiquitin-specific peptidase (USP), plays an important role in many cellular processes through its catalytic deubiquitination of various substrates. However, its nuclear function to shape the transcriptional network in mouse embryonic stem cells (mESCs) remains poorly understood. Here, we report that USP7 maintains mESCs identity through both catalytic activity-dependent and -independent repression of lineage differentiation genes. Usp7 depletion attenuates SOX2 level and derepresses lineage differentiation genes thereby compromising mESCs pluripotency. Mechanistically, USP7 deubiquitinates and stabilizes SOX2 to repress mesoendodermal (ME) lineage genes. Moreover, USP7 assembles into RYBP-variant Polycomb repressive complex 1 and contributes to Polycomb chromatin-mediated repression of ME lineage genes in a catalytic activity-dependent manner. Importantly, USP7 deficient in its deubiquitination function is able to maintain RYBP binding to chromatin for repressing primitive endoderm-associated genes. Overall, our study demonstrates that USP7 harbors both catalytic and non-catalytic activity to repress different lineage differentiation genes thereby revealing a previously unrecognized role in controlling gene expression for maintaining mESCs identity.
2023-07-20 | PXD039633 | Pride
Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation. Embryonic Stem Cell (ESC) lines mutant for PRC2 core components Suz12 (Suz12GT and Suz12delta) and Eed (Eednull) were subjected to in vitro directed differentiation down the spinal motor neuron lineage. ESCs and day 5 differentiated cells from the three mutant lines and wild-type were used for Reduced Representation Bisulfite Sequencing (RRBS).
2014-11-17 | E-GEOD-53507 | biostudies-arrayexpress
Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation. Embryonic Stem Cell (ESC) lines mutant for PRC2 core components Suz12 (Suz12GT and Suz12delta) and Eed (Eednull) were subjected to in vitro directed differentiation down the spinal motor neuron lineage. ESCs and day 5 differentiated cells from the three mutant lines and wild-type were used for RNA-seq.
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Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation. Embryonic Stem Cell (ESC) lines mutant for PRC2 core components Suz12 (Suz12GT and Suz12delta) and Eed (Eednull) were subjected to in vitro directed differentiation down the spinal motor neuron lineage. ESCs and day 5 differentiated cells from the three mutant lines and wild-type were used for H3K27me3 ChIP-seq.
2014-11-17 | E-GEOD-53505 | biostudies-arrayexpress
Project description:Linker histone H1 binds to the nucleosome and is implicated in the regulation of the chromatin structure and function. The H1 variant H1FOO is heavily expressed in oocytes and early embryos. However, given the poor homology of H1FOO among mammals, the functional role of H1FOO during early embryonic development remains largely unknown, especially in domestic animals. Here, we find that H1FOO is not only expressed in oocytes and early embryos but granulosa cells and spermatids in cattle. We then demonstrate that the interference of H1FOO results in early embryonic developmental arrest in cattle using either RNA editing or Trim-Away approach. H1FOO depletion leads to compromised expression of critical lineage-specific genes at the morula stage and affects the establishment of cell polarity. Interestingly, H1FOO depletion causes a significant increase in expression genes encoding other linker H1 and core histones. Concurrently, there is an increase of H3K9me3 and H3K27me3, two markers of repressive chromatin and a decrease of H4K16ac, a marker of open chromatin. Importantly, overexpression of bovine H1FOO results in severe embryonic developmental defects. In sum, we propose that H1FOO controls the proper chromatin structure that is crucial for the fidelity of cell polarization and lineage specification during bovine early development.
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Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation.
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Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation.
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Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation, an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, which presents a major roadblock for dissecting the precise roles of PRC2 activity during lineage commitment. While recent studies suggest that loss of H3K27me3 leads to changes in DNA methylation in ESCs, how these two pathways coordinate to regulate gene expression programs during lineage commitment is poorly understood. Here, we analyzed gene expression and DNA methylation levels in several PRC2 mutant ESC lines that maintain varying levels of H3K27me3. We found that maintenance of intermediate levels of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). However, genes that function to specify other lineages failed to be repressed, suggesting that PRC2 activity is necessary for lineage fidelity. We also found that H3K27me3 is antagonistic to DNA methylation in cis. Furthermore, loss of H3K27me3 leads to a gain in promoter DNA methylation in developmental genes in ESCs and in lineage genes during differentiation. Thus, our data suggest a role for PRC2 in coordinating dynamic gene repression while protecting against inappropriate promoter DNA methylation during differentiation.
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Project description:Spermatogenesis is the process by which spermatogonial stem cells differentiate into haploid spermatozoa. During this process, multiple testis-specific histone variants are involved in the dynamic chromatin transitions. H2BFWT is a testis-specific H2B variant only found in primates, and several reports showed that single-nucleotide polymorphisms (SNPs) of H2BFWT are associated with male non-obstructive infertility. Different from another testis-specific variant TH2B, H2BFWT is preferentially localized in sub-telomeric regions and the promoter regions of testicular high expression genes during the transition from differentiated spermatogonia to early spermatocytesspermatogenesis. Cryo-EM structural analysis shows that the H2BFWT nucleosome is defined by weakened interactions between H2A-H2BFWT dimer and H4, and between the histone octamer and DNA. WIn addition, we found that the shape of the H2A L1 loops was also changed by the presence of H2BFWT. Furthermore, our structural model shows that H2BFWTH100R, which is one of the SNPs associated with infertility, further destabilizes the nucleosome and increases the nucleosome unwrapping rate by interfering with the interaction with H4K91. Taken together, our results suggest that H2BFWT may be necessary for the regulation of spermatogenesis-related genes transcription in spermatogonia by decreasing RNA polymerase II transcription barriers, and that the H100R mutation overdrives its nucleosome-destabilizing effects which likely explain how it causes infertility.
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