A new family of vertebrate-specific Polycombs encoded by the Lcor/Lcorl genes balance PRC2 subtype activities

Abstract

The Polycomb Repressive Complex 2 (PRC2) is composed of the 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 addition, several highly conserved sub-stoichiometric accessory proteins associate with PRC2, including AEBP2, JARID2, EPOP and PCL1-3. However, little is known about the division of labour amongst these cofactors or how they confer the diverse roles of the PRC2 complex. Here we report the discovery of a new family of vertebrate specific PRC2 associated proteins; ?Polycomb associated LCOR isoform 1? (PALI1) and PALI2, which are novel isoforms of the LCOR and LCORL genes, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and shares a unique PRC2 interaction domain with PALI2 that emerged during vertebrate evolution. The PALI proteins define a unique subset of PRC2 complexes that lack AEBP2 and JARID2. We uncover a biochemical and genetic antagonism between the Pali1/2 proteins and Aebp2 in mouse embryonic stem cells, consistent with an essential role for Pali1/2 during differentiation. In summary, we identify a new family of vertebrate specific PRC2 proteins and reveal an unexpected antagonism between sub-stoichiometric subunits of the PRC2 complex suggesting that alternative complexes may have opposing effects on transcriptional regulation.