Deciphering the role of cis-regulatory elements and TFAP2C in the activation of zygotic Sox2 expression in mouse preimplantation embryos.

Cell fate decisions in preimplantation embryos require the coordinated expression of pluripotency and lineage-specific transcription factors. SOX2 represents the first pluripotency regulator for which expression is restricted to the inside cells of mouse preimplantation embryos. However, the genetic mechanisms that activate the expression of zygotic Sox2 are poorly understood. Here, we report that Sox2 expression in mouse embryos is controlled by the actions of key cis-regulatory elements, including a proximal promoter and super enhancer. We show that TFAP2C, a key trophoblast lineage regulator, binds to the Sox2 proximal promoter to activate its expression. Lastly, we provide evidence that TFAP2C and the HIPPO signaling pathway cooperatively regulate Sox2 expression. In summary, this work has important implications for understanding how conventional trophoblast transcription factors, such as TFAP2C, contribute to the activation of early pluripotency genes to facilitate divergent cellular states that support lineage formation.