NELFA supports naïve pluripotency and drives 8C-like state in human embryonic stem cells

A minority of 8C-like cells (8CLCs) expressing zygotic genome activation genes are captured in naïve embryonic stem cells (ESCs). However, how human ESCs transition into 8CLCs remains unknown. Here, we show that NELFA is dispensable in human primed ESCs but critical for naïve pluripotency, and its overexpression promotes the primed-to-naïve conversion. Notably, NELFA robustly induces 8CLCs that express human ZGA-specific genes in naïve ESCs. NELFA-induced human 8CLCs can contribute to both embryonic and extraembryonic developmental potential in the interspecies human-mouse chimera assay. Importantly, we also discovered that TP53 can activate the human 8CLCs state, and NELFA might be an upstream regulator of TP53. Furthermore, TP53 and NELFA are both essential for the complete transition to the 8CLC state. We also demonstrate that sustained NELFA overexpression in primed ESCs directs neural lineage specification. Thus, NELFA establishes and maintains naïve pluripotency and drives the 8CLC state, providing insights into early human embryogenesis.