Phase separation of Polycomb-like (PCL) proteins drive PRC2 complex condensates to regulate gene expression

Polycomb group (PcG) proteins function as two major multicomponent protein complexes: Polycomb repressive complex 1 (PRC1) and 2 (PRC2) to repress key developmental genes and maintain epigenetic memory of cell identity during development. Phase-separation has long been implicated in PRC1 mediated gene silencing, but it is still unclear whether PRC2 also utilize a similar mechanism to regulate gene expression. Here we report that Polycomb-like (PCL) proteins, PRC2 accessory factors, can phase-separate in vitro and generate dynamic puncta in vivo . Biochemical and cellular analyses reveal that PCL proteins (hereafter referred to as PCLs) have intramolecular interaction between N- and C-terminal domains, which make PCLs into more compact conformations. The intramolecular interaction not only controls the size of the PCLs phase separation droplets, but also affects the chromatin association of PRC2. Finally, we show that CpG islands, key DNA regulatory elements in mammalian promoters, disrupt the N-C intramolecular interaction of PCLs to expose their middle intrinsically disordered regions (IDRs), which in turn trigger PCLs driven PRC2 condensates formation. Together, this study provides a new perspective on the regulation of PRC2 by PCLs, implicating PCLs ‘read’ CpG islands to fine-tune their oligomerization to overcome the threshold for PRC2 recruitment to corresponding genomic loci via multivalent interaction with CpG islands chromatin.