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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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