Modularity of OCT4 underlies its functional diversity in reprogramming and embryonic development (mES ATAC-seq)

Amongst the multiple cell fates orchestrated by OCT4, its ability to maintain pluripotency is thought to underpin reprogramming. How OCT4 drives pluripotency from diverse cellular contexts is unclear. By systematically dissecting OCT4, we find that reprogramming requires OCT4 domains dispensable for pluripotency maintenance and development throughout gastrulation but important for the embryo competence to develop through late gestation. Removing OCT4 essential domains in reprogramming leads to more non-specific OCT4 enrichment at accessible somatic sites, unlike removing the non-essential domains, which expands genomic targeting of closed pluripotency sites. Delineating the interaction of OCT4 with chromatin-associated proteins in reprogramming and pluripotency maintenance reveals that OCT4 essential domains engage a unique set of proteins during reprogramming. Remarkably, OCT4 can induce pluripotent and trophoblast stem cells using many similar domains and yet it can be truncated to only induce pluripotency. Our findings demonstrate that the ability of transcription factors to control diverse cell types is encoded within their modular nature.