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

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. Overall design: RNA seq analysis of Pali WT, Pali1 KO, Pali1/2 double KO, C129 WT and Aebp2 gene trap mouse embryonic stem cells at three time points (Day 0, Day 4 and Day 8) during embryoid body differentiation (EB). 30 samples are included. Biological duplicates are present.

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Conway E, Jerman E, Healy E, Ito S, Holoch D, Oliviero G, Deevy O, Glancy E, Fitzpatrick DJ, Mucha M, Watson A, Rice AM, Chammas P, Huang C, Pratt-Kelly I, Koseki Y, Nakayama M, Ishikura T, Streubel G, Wynne K, Hokamp K, McLysaght A, Ciferri C, Di Croce L, Cagney G, Margueron R, Koseki H, Bracken AP