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Expression regulation by Pcgf1 in mouse embryonic stem cells

ABSTRACT: The Polycomb repressive complex 1 (PRC1) is essential for fate decisions of embryonic stem (ES) cells. Emerging evidence suggests that six major variants of PRC1 complex, defined by the mutually exclusive presence of Pcgf subunit, regulate distinct biological processes, yet very little is known about the mechanism by which each version of PRC1 instructs and maintains cell fate. Here, we disrupted the Pcgf1, also known as Nspc1 and one of six Pcgf paralogs, in mouse ES cells by the CRISPR/Cas9 technology. We showed that although these mutant cells were viable and retained normal self-renewal, they displayed severe defects in differentiation in vitro. To gain a better understanding of the role of Pcgf1 in transcriptional control of differentiation, we analysed mRNA profiles from Pcgf1 deficient cells using RNA-seq. In contrast to the canonical role of PRC1 in gene repression, we found that Pcgf1 mainly functioned as a transcriptional activator to drive expression of many genes involved in ectoderm and mesoderm differentiation. Chromatin immunoprecipitation experiments demonstrated that Pcgf1 deletion caused a decrease in Ring1B and its associated H2AK119ub1 mark binding to target genes. Altogether, our results revealed an unexpected function of Pcgf1 in gene activation during ES cell maintenance.

ORGANISM(S): Mus musculus

PROVIDER: GSE95383 | GEO | 2017/06/13

REPOSITORIES: GEO

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Next-Generation Sequencing Facilitates Quantitative Analysis of WT, Ring1a-/-, Ring1b-/-, Ring1a/b-/-, Pcgf1/3/5/6-/- and Pcgf1/2/3/4/5/6-/- Embryonic Stem Cells Transcriptomes

Project description:Polycomb repressive complexes (PRC) are epigenetic transcriptional repressors by establishing facultative heterochromatin repressive domains and play an essential role in numerous developmental processes. PRC1, which contains the E3 ligases RING1A/B and deposits H2AK119ub, forms six biochemically subcomplexes (PRC1.1-PRC1.6) based on the assembled PCGF protein (PCGF1–PCGF6), and has been involved in the maintenance of embryonic stem (ES) cell state. More recent evidence indicates that PCGF family participates in the self-renewal and pluripotent maintenance. However, it is still enigmatic that how the PCGF family engaged in the controlling process. Here, we generate the Ring1a-/-, Ring1b-/-, Ring1a/b-/-, Pcgf1/3/5/6-/- and Pcgf1/2/3/4/5/6-/- ES cells using CRISPR/Cas9 technique and CRE-LoxP recombination system to discover the central determinants in PCGF family-related biological process.

2022-09-01 | GSE183646 | GEO

Variant PCGF1-PRC1 links PRC2 recruitment with induced transcriptional inactivation at target genes [RNA-seq]

Project description:Polycomb repressive complexes-1 and -2 (PRC1 and 2), silence developmental genes in spatiotemporally regulated manner during metazoan embryogenesis. How PcG proteins contribute to down-regulation of target genes upon differentiation, however, remains elusive. Here, by differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role of a PCGF1 (Polycomb group RING finger protein 1)-containing variant PRC1 complex (PCGF1-PRC1) to facilitate induced down-regulation of a group of genes. Binding of PCGF1-PRC1 results in down-regulation of transcriptional activity, followed by Histone H2AK119 mono-ubiquitination (H2AK119ub1) and subsequent recruitment of PRC2, to initiate PcG-repressive domain formation. Based on these findings, we propose that PCGF1-PRC1 mediates establishment of PcG-repressive domains at target genes during differentiation.

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Variant PCGF1-PRC1 links PRC2 recruitment with induced transcriptional inactivation at target genes [CUT&Tag]

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Variant PCGF1-PRC1 links PRC2 recruitment with induced transcriptional inactivation at target genes [ChIP-seq]

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PCGF5 is required for neural differentiation of embryonic stem cells [ChIP-seq]

Project description:Polycomb-group proteins are key regulators of the transcriptional programs that maintain stem cell identity and dictate lineage specification. Polycomb repressor complex 1 (PRC1) contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1) to regulate gene expression. PRC1 has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we find that Pcgf5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-β signaling pathway. Inhibition of SMAD2/TGF-β signaling or rescue by overexpression of Pcgf5 can restore the capability of mESCs to differentiate towards a neural cell fate. PCGF5 works by stimulating RING1B-dependent H2AK119ub1 both in vitro and in vivo, leading to the suppression of TGF-β signaling genes. PCGF5 loss-of-function prevents the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results showed that PCGF5 might function as both a repressor for SMAD2/TGF-β signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate.

2018-03-10 | GSE107377 | GEO

PCGF5 is required for neural differentiation of embryonic stem cells [RNA-seq]

2018-03-10 | GSE95127 | GEO

PCGF Homologs and RYBP Define Functionally Distinct PRC1 Family Complexes

Project description:The heterogeneous nature of mammalian PRC1 complexes has hindered our understanding of their biological functions. Here, we present a comprehensive proteomic and genomic analysis that uncovered six major groups of PRC1 complexes each containing a distinct PCGF subunit, a RING1A/B ubiquitin ligase, and a unique set of associated polypeptides. These PRC1 complexes differ in their genomic localization and only a small subset co-localize with H3K27me3. Further biochemical dissection revealed that the six PCGF–RING1A/B combinations form multiple complexes through association with RYBP or its homolog YAF2, which prevents the incorporation of other canonical PRC1 subunits such as CBX, PHC and SCM. Although both RYBP/YAF2- and CBX/PHC/SCM-containing complexes compact chromatin, only RYBP stimulates the activity of RING1B toward H2AK119ub1, suggesting a central role in PRC1 function. Knockdown of RYBP in ES cells compromised their ability to form embryoid bodies, likely because of defects in cell proliferation and maintenance of H2AK119ub1 level.

2012-02-09 | GSE34774 | GEO

PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment

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.

2022-11-30 | PXD036330 | Pride

PCGF Homologs and RYBP Define Functionally Distinct PRC1 Family Complexes

Project description:The heterogeneous nature of mammalian PRC1 complexes has hindered our understanding of their biological functions. Here, we present a comprehensive proteomic and genomic analysis that uncovered six major groups of PRC1 complexes each containing a distinct PCGF subunit, a RING1A/B ubiquitin ligase, and a unique set of associated polypeptides. These PRC1 complexes differ in their genomic localization and only a small subset co-localize with H3K27me3. Further biochemical dissection revealed that the six PCGFM-bM-^@M-^SRING1A/B combinations form multiple complexes through association with RYBP or its homolog YAF2, which prevents the incorporation of other canonical PRC1 subunits such as CBX, PHC and SCM. Although both RYBP/YAF2- and CBX/PHC/SCM-containing complexes compact chromatin, only RYBP stimulates the activity of RING1B toward H2AK119ub1, suggesting a central role in PRC1 function. Knockdown of RYBP in ES cells compromised their ability to form embryoid bodies, likely because of defects in cell proliferation and maintenance of H2AK119ub1 level. ChIP-seq experiments of different PRC1 components were performed either on HA-tagged transgenic stable 293T-REx lines or on endogenous subunits using specific antibodies.

2012-02-09 | E-GEOD-34774 | biostudies-arrayexpress

Gene regulation by PCGF1 in hematopoietic progenitor cells

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