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A New Family of Vertebrate Specific Polycomb Proteins Encoded by the LCOR and LCORL Gene Loci Reveal Antagonism Between PRC2 Subtypes

ABSTRACT: The Polycomb Repressive Complex 2 (PRC2) is composed of core subunits SUZ12, EED, RBBP4/7 and EZH1/2, which together are responsible for all di- and tri- methylation of lysine 27 on Histone H3 (H3K27me2/3) in higher eukaryotes. While two distinct forms, PRC2.1 (containing one Polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2) exist, little is known about their differential functions or interplay. Here we report the discovery of a new family of vertebrate specific PRC2.1 associated proteins; ‘PRC2 associated LCOR isoform 1’ (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. We uncover an antagonistic relationship between the PALI-PRC2.1 and AEBP2-PRC2.2 subtypes and establish that both are required for balanced regulation of Polycomb target genes during differentiation. This discovery links the Polycomb epigenetic system with co-repressors and nuclear receptors in the regulation of cellular identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE108302 | GEO | 2018/04/05

REPOSITORIES: GEO

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A New Family of Vertebrate Specific Polycomb Proteins Encoded by the LCOR and LCORL Gene Loci Reveal Antagonism Between PRC2 Subtypes

Project description:The Polycomb Repressive Complex 2 (PRC2) is composed of core subunits SUZ12, EED, RBBP4/7 and EZH1/2, which together are responsible for all di- and tri- methylation of lysine 27 on Histone H3 (H3K27me2/3) in higher eukaryotes. While two distinct forms, PRC2.1 (containing one Polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2) exist, little is known about their differential functions or interplay. Here we report the discovery of a new family of vertebrate specific PRC2.1 associated proteins; ‘PRC2 associated LCOR isoform 1’ (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. We uncover an antagonistic relationship between the PALI-PRC2.1 and AEBP2-PRC2.2 subtypes and establish that both are required for balanced regulation of Polycomb target genes during differentiation. This discovery links the Polycomb epigenetic system with co-repressors and nuclear receptors in the regulation of cellular identity.

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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) 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.

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