Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human naive pluripotent cell reprogramming

Uncovering the mechanisms that establish naive pluripotency in humans is crucial for the future applications of pluripotent stem cells including the production of human blastoids. However, the regulatory pathways that control the establishment of naive pluripotency by reprogramming are largely unknown. Here, we use genome-wide screening to identify essential regulators as well as major impediments of human primed to naive pluripotent stem cell reprogramming. We discover that factors essential for cell state change do not typically undergo changes at the level of gene expression but rather are repurposed with new functions. Mechanistically, we establish that the variant Polycomb complex PRC1.3 and PRDM14 jointly repress developmental and gene regulatory factors to ensure naive cell reprogramming. In addition, small-molecule inhibitors of reprogramming impediments improve naive cell reprogramming beyond current methods. Collectively, this work defines the principles controlling the establishment of human naive pluripotency and also provides new insights into mechanisms that destabilize and reconfigure cell identity during cell state transitions.