SOX2 terminates trophectoderm competence in inner cell mass by closing trophectoderm enhancers

During embryonic development, cellular competence to respond to differentiation signals changes dynamically. Although the mechanisms underlying competence acquisition have been extensively studied, those underlying competence loss remain unclear. In preimplantation mouse embryos, Hippo signaling shifts from regulating trophectoderm (TE) fate specification to promoting epiblast maturation. During the blastocyst stage, inner cell mass (ICM) cells lose TE competence in response to the Hippo signaling effector TEAD– YAP. Here, we show that the pioneer factor SOX2 terminates TE competence in the ICM. SOX2 binding to the TEAD–YAP-dependent TE enhancer (TEE) of the TE regulator Gata3 induces chromatin closure, suppressing TEE responsiveness to TEAD–YAP activity. This function of SOX2 requires its interaction with the corepressor TLE4 and histone deacetylase. Similar SOX2-dependent chromatin closure also occurs around other TE genes, including the TE enhancer of another TE regulator, Cdx2 . Thus, SOX2 terminates TE competence in ICM cells by closing Hippo signaling-responsive enhancers.