INO80 promotes H2A.Z occupancy to regulate 1 cell fate transition in pluripotent stem cells

The INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role in pluripotency and cell fate transition is not fully defined. We examined the impact of Ino80 deletion in the naive and primed pluripotent stem cells. We found that Ino80 deletion had minimal effect on self-renewal and gene expression in the naive state, but led to cellular differentiation and de-repression of developmental genes in the transition toward and maintenance of the primed state. Mechanistically, INO80 pre-marked gene promoters that would adopt the H3K4me3 and H3K27me3 bivalent histone modifications. It promoted H2A.Z occupancy at these future bivalent domains to facilitate H3K27me3 installation and maintenance as well as downstream gene repression. Thus, INO80-dependent H2A.Z occupancy is a critical a licensing step for bivalency and poised gene expression in pluripotent stem cells. Our results uncovered an unexpected function of INO80 in H2A.Z deposition and gene repression, and an epigenetic mechanism by which chromatin remodeling, histone variant and modification coordinately control cell fate.