The ETS Transcription Factor ERF controls the exit from the naïve pluripotent state

The naïve epiblast undergoes a transition to a pluripotent primed state during embryo implantation. Despite the relevance of the FGF pathway during this period, little is known about the downstream effectors regulating this signaling. Here, we examined the molecular mechanisms coordinating the naïve to primed transition by using inducible ESC to genetically eliminate all RAS proteins. We show that differentiated RASKO ESC remain trapped in an intermediate state of pluripotency with naïve-associated features. Elimination of the transcription factor ERF overcomes the developmental blockage of RAS-deficient cells by naïve enhancer decommissioning. Mechanistically, ERF regulates NANOG expression and ensures naïve pluripotency by strengthening naïve transcription factor binding at ESC enhancers. Moreover, ERF negatively regulates the expression of the de novo methyltransferase DNMT3B, which participates in the extinction of the naïve transcriptional program. Collectively, we demonstrated an essential role for ERF controlling the exit from naïve pluripotency during the progression to primed pluripotency.TeaserERF is the MAPK-dependent switch controlling the transition between naïve and primed pluripotency during embryonic development.