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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE199527 | GEO | 2023/04/06

REPOSITORIES: GEO

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PRC2.1 and PRC2.2 Specific Accessory Proteins Drive Recruitment of Different Forms of Canonical PRC1 [4C-seq]

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

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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 [ChIP-seq]

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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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Project description:Polycomb repressive complex 2 (PRC2) silences expression of developmental transcription factors in pluripotent stem cells by methylating lysine 27 on histone H3. Two mutually exclusive subcomplexes, PRC2.1 and PRC2.2, are defined by the set of accessory proteins bound to the core PRC2 subunits. Here we introduce separation-of-function mutations into the SUZ12 subunit of PRC2 to drive it into a PRC2.1 or 2.2 subcomplex in human induced pluripotent stem cells (iPSCs). We find that PRC2.2 occupies polycomb target genes at low levels and that homeobox transcription factors are upregulated when this complex is exclusively present. In contrast with previous studies, we find that chromatin occupancy of PRC2 increases drastically when it is forced to form PRC2.1. Additionally, several cancer-associated mutations also coerce formation of PRC2.1. We suggest that PRC2 chromatin occupancy can be altered in the context of disease or development by tuning the ratio of PRC2.1 to PRC2.2.

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