PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1

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 (KO) 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 catalyzes 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 catalyzing 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. [Display omitted] •PRC2.1/PRC2.2 are co-recruited to promote de novo Polycomb target gene repression•PRC2.1 binds in sharp peaks and specializes in CBX2/4-cPRC1 recruitment•PRC2.2 binds in broader H2AK119ub1-like profiles and has weak H3K27me3 acivity•PRC2.2 component JARID2 specializes in CBX7-cPRC1 recruitment Glancy et al. reveal divergent molecular functions of PRC2 subcomplexes, PRC2.1 and PRC2.2, in mediating Polycomb target gene repression. PRC2.1 promotes the recruitment of CBX2/4-cPRC1 via H3K27me3 deposition, while PRC2.2 component JARID2 specializes in driving the recruitment of CBX7-cPRC1. These findings go a long way toward explaining why these two independent PRC2 subcomplexes have persisted throughout evolution.