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Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

ABSTRACT: Polycomb Repressive Complex 2 (PRC2) plays an essential role in gene repression during development, catalysing H3 lysine 27 trimethylation (H3K27me3). MTF2 in the PRC2.1 sub-complex, and JARID2 in PRC2.2, are central in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). To investigate how PRC2.1 and PRC2.2 cooperate, we combined Polycomb mutant mESCs with chemical inhibition of binding to H3K27me3. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, which are mutually reinforced. Whereas PRC2.1 recruitment is mediated by MTF2 binding to DNA, JARID2-containing PRC2.2 recruitment is more dependent on PRC1. Both recruitment axes are supported by core subunit EED binding to H3K27me3, but EED inhibition exhibits a more pronounced effect in Jarid2 null cells. Finally, we show that PRC1 and PRC2 enhance reciprocal binding. Together, these data disentangle the interdependent interactions that are important for PRC2 recruitment.

ORGANISM(S): Mus musculus

PROVIDER: GSE133085 | GEO | 2020/08/06

REPOSITORIES: GEO

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Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.

2020-08-07 | PXD014290 | Pride

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

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Variant PRC2.1 and PRC2.2 co-operate to direct H3K27 methylations in ESCs [ChIP-seq]

Project description:Polycomb repressive complex 2 (PRC2) is composed of EED, SUZ12, and EZH1/2, and mediates mono-, di- and tri-methylation of Histone H3 at Lysine 27. While, two subcomplexes defined by their specific accessory proteins, termed PRC2.1 (Polycomb-like proteins 1-3, EPOP and PALI1/2) and PRC2.2 (AEBP2 and JARID2) exist, little is known about their differential functions. Here, we show that PRC2.1 and PRC2.2 share the majority of their target genes in mouse embryonic stem cells (ESCs). While loss of all three Polycomb-like proteins (PHF1, MTF2, PHF19) leads to eviction of EPOP and PALI1 from chromatin, PRC2.2 specific components are maintained together with SUZ12 and H3K27me3 at broad Polycomb domains. We show that PRC2.2 localises to PRC1 mediated H2AK119ub1 at these broad Polycomb domains to maintain H3K27me3, even in the absence of PRC2.1. Taken together, these data establish that PRC2.1 and PRC2.2 co-operate to direct H3K27me3, but have independent recruitment mechanisms.

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Variant PRC2.1 and PRC2.2 co-operate to direct H3K27 methylations in ESCs [RNA-seq]

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PRC2.1 and PRC2.2 Specific Accessory Proteins Drive Recruitment of Different Forms of Canonical PRC1

Project description:Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear. Through genetic knockout and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyses the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1, but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalysing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes. We therefore define distinct contributions of PRC2.1 and PRC2.2 specific accessory proteins to Polycomb mediated repression and uncover a new mechanism for cPRC1 recruitment.

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PRC2.1 and PRC2.2 synergize to co-ordinate H3K27 tri-methylation.

Project description:Polycomb Repressive Complex 2 (PRC2) is composed of EED, SUZ12, and EZH1/2 and mediates mono-, di- and tri-methylation of Histone H3 at Lysine 27. While at least two subcomplexes exist, defined by their specific accessory proteins, termed PRC2.1 (Polycomb-like proteins 1-3, EPOP and PALI1/2) and PRC2.2 (AEBP2 and JARID2), little is known about their differential functions. Here, we show that PRC2.1 and PRC2.2 share the majority of target genes in mouse embryonic stem cells (ESCs). The loss of all three Polycomb-like proteins is sufficient to destabilise and evict PRC2.1 from chromatin, but also leads to reduced PRC2.2 and H3K27me3 at most Polycomb domains. However, the combined loss of PRC2.1 and PRC2.2 is necessary to completely remove H3K27me3 at broad Polycomb domains such as the Hox loci. Our data support a model in which the specific accessory proteins within PRC2.1 and PRC2.2 co-operate to direct and maintain H3K27me3, via both synergistic and independent mechanisms.

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Jarid2 and PRC2, Partner in Regulating Gene Expression

Project description:The Polycomb Group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the PRC2 complex including the histone H3 lysine 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We find that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in co-recruitment of PRC2 with resultant increased levels of H3K27me2/3. Jarid2 co-localizes with Ezh2 and MTF2, a homologue of Drosophila Pcl, at endogenous genes in ES cells. Jarid2 can itself bind DNA and its recruitment in ES cells is interdependent with that of PRC2 as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing. Examination of two factors in ES cells

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