PRC2.1 and PRC2.2 Specific Accessory Proteins Drive Recruitment of Different Forms of Canonical PRC1
Description
PRC2.1 and PRC2.2 Specific Accessory Proteins Drive Recruitment of Different Forms of Canonical PRC1. Eleanor Glancy1*, Cheng Wang1*, Ellen Tuck1, Evan Healy1, Simona Amato2, Hannah K. Neikes3, Andrea Mariani2, Marlena Mucha1, Michiel Vermeulen3, Diego Pasini2,4, Adrian P. Bracken1,5. 1Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. 2IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, Italy. 3Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands. 4University of Milan, Via A. di Rudini 8, Department of Health Sciences, 20142 Milan, Italy. *These authors contributed equally. 5Lead Contact. *Corresponding author: Adrian P. Bracken (adrian.bracken@tcd.ie). Summary: Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is believed to direct recruitment of canonical PRC1 (cPRC1) 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 and replacement of PRC2 subcomplex-specific accessory proteins, we discover that PRC2.1 and PRC2.2 function through distinct mechanisms. During the transition from naïve to primed pluripotency, PRC2.1 accumulates in sharp defined peak-like profiles at CpG islands, dependent on the DNA and histone modification binding activities of MTF2. In contrast, PRC2.2 is recruited in broader profiles, mirroring H2AK119ub1 accumulation, dependent on the ubiquitin-binding abilities of JARID2 and AEBP2. Surprisingly, we uncover distinct roles for PRC2.2 and PRC2.1 specific accessory proteins in specifically mediating the recruitment of either CBX7- or CBX2/4- containing canonical PRC1 (cPRC1), respectively. PRC2.1 mediates the majority of H3K27me3 deposition at Polycomb target genes, which is sufficient to promote recruitment of CBX2/4-cPRC1, but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at mediating H3K27me3 deposition, we find that JARID2 is essential for recruitment of CBX7-cPRC1 and its 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 distinct mechanisms for cPRC1 recruitment. Highlights • PRC2.1/PRC2.2 are co-recruited to promote de novo Polycomb target gene repression. • PRC2.1 binds in sharp peaks specialising in H3K27me3 deposition and CBX2/4-cPRC1 recruitment. • PRC2.2 binds in broader H2AK119ub1-like profiles and has weak H3K27me3 acivity. • PRC2.2 component JARID2 specifically recruits CBX7-cPRC1. Keywords: Polycomb, PRC2.1, PRC2.2, H3K27me3, JARID2, Polycomb-like protein, PRC1, CBX2, CBX4, CBX7.