Poising and connectivity of emergent human developmental enhancers in the transition from naive to primed pluripotency - RNA-seq

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. We find that enhancer poising emerges early in the transition, while the contacts show diverse dynamics that is only partially coupled to poising. 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.