Dynamics of poised enhancer connectivity upon PRC2 perturbation during the naive-to-primed transition of human pluripotent stem cells

In contrast, these poised enhancers (PEs) are scarce in naive hPSCs that model pre-implantation epiblast. PEs form abundant chromosomal contacts with developmental genes, but when these contacts emerge, how their formation relates to enhancer poising and their functional significance remains incompletely understood.

Here, we devise high-resolution, PE-targeted Capture Hi-C to generate a comprehensive atlas of PE chromosomal contacts in the time course of hPSC transition from the naive to primed state. In this experiment, we show that PROTAC-induced degradation of Polycomb Repressive Complex 2 (PRC2) early in the transition weakens PE connectivity, while inhibition of its H3K27 methyltransferase activity does not, suggesting a non-catalytic role of Polycomb in supporting PE contacts.