Canonical PRC1 Recruitment is Promoted by EZH1-PRC2 Independent of H3K27me3 in Quiescent Cells

Polycomb Repressive Complex 2 (PRC2) is composed of core subunits EED, SUZ12 and either EZH1 or EZH2, and is essential for maintenance of cellular identity in multicellular organisms. PRC2 mediated H3K27me3 is believed to serve as a docking site to recruit canonical PRC1 (cPRC1), which then facilitates gene repression. Here, we discover that EZH1-PRC2 does not mediate H3K27me3 in quiescent cells where it is predominant, thereby rendering these non-proliferating cells refractory to PRC2 inhibitors. While PROTAC mediated degradation of EZH1-PRC2 in quiescent cells does not reduce H3K27me3 levels, it partially displaces cPRC1. Further uncoupling the dependence of cPRC1 on H3K27me3, we show that cPRC1 is exclusively bound together with PRC2 at target sites and does not bind to the majority of H3K27me3 dispersed throughout the genome. Our results uncover an unexpected interplay between cPRC1 and PRC2 that is independent of H3K27me3, while also providing a cautionary note for the use of PRC2 inhibitors in the treatment of cancers that contain non-proliferating cells.