The ETS transcription factor ERF controls the exit from the naïve pluripotent state in a MAPK-dependent manner

The naïve 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 naïve to primed...

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Bibliographic Details
Published in:Science advances 2021-10, Vol.7 (40), p.eabg8306-eabg8306
Main Authors: Vega-Sendino, Maria, Olbrich, Teresa, Tillo, Desiree, Tran, Andy D, Domingo, Catherine N, Franco, Mariajose, FitzGerald, Peter C, Kruhlak, Michael J, Ruiz, Sergio
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Developmental Biology
SciAdv r-articles
Signal Transduction
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Summary:The naïve 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 naïve to primed transition by using inducible ESC to genetically eliminate all RAS proteins. We show that differentiated RAS 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 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 in a MAPK-dependent manner during the progression to primed pluripotency.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abg8306