Emerging cooperativity between Oct4 and Sox2 governs the pluripotency network in mouse embryos

During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 are globally dispensable in morulae. Oct4 and Sox2 come into play in the early ICM, coinciding with the initiation of Sox2 expression, and they directly activate the pluripotency-related genes and the corresponding OCT-SOX enhancers. Sox2 KO failed to activate the ICM-specific pluripotency-related genes while overexpression of Sox2 prematurely upregulated these genes in morulae, suggesting that Sox2 acts as a limiting factor for inducing the pluripotent network. Our study provides new insights into this critical process of mouse preimplantation development at molecular levels.