The Ets Transcription Factor Erf Controls The Exit From The Naive Pluripotent State In A Mapk-Dependent Manner

The naive epiblast transitions 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 naive to primed transition by using inducible ESC to genetically eliminate all RAS proteins. We show that differentiated RAS(KO) ESC remain trapped in an intermediate state of pluripotency with naive-associated features. Elimination of the transcription factor ERF overcomes the developmental blockage of RAS-deficient cells by naive enhancer decommissioning. Mechanistically, ERF regulates NANOG expression and ensures naive pluripotency by strengthening naive transcription factor binding at ESC enhancers. Moreover, ERF negatively regulates the expression of the methyltransferase DNMT3B, which participates in the extinction of the naive transcriptional program. Collectively, we demonstrated an essential role for ERF controlling the exit from naive pluripotency in a MAPK-dependent manner during the progression to primed pluripotency.