Oct4 shuffles Sox partners to direct cell fate.

The transcription factor Oct4 plays a crucial role in the maintenance of the embryonic pluripotent state, but can also regulate early lineage commitment. In this issue of The EMBO Journal, Aksoy et al (2013) lend critical mechanistic insights into the ability of Oct4 to regulate and specify the primitive endodermal lineage. These regulatory actions are governed by alternative direct partnering of Oct4 with Sox17, instead of Sox2, that leads to global reprogramming of enhancer occupancy by Oct4 during primitive endoderm differentiation. The process of how cell fates are acquired and maintained in multicellular organisms continues to be a major focus of biological research for over a century. The remarkable ability of progenitor cells to acquire a broad range of identities is mediated, in part, by the presence of distinct cis-regulatory elements throughout the genome, termed Enhancers. The latter control the spatial and temporal expression pattern of specific set of genes. Pluripotent embryonic stem cells (ESCs), which are derived from the inner cell mass (ICM) and have the ability to grow indefinitely while maintaining their differentiation capacity, constitute a unique tool for modelling cell fate choices in the Petri dish. The maintenance of pluripotency is governed by a network of transcription factors, including Oct4, Sox2 and Nanog, which repress genes that promote differentiation and activate genes that maintain pluripotency (Yamanaka et al, 2006; Hanna et al, 2010). Oct4 and Sox2 interact physically and cooperatively bind to DNA at genes enhancer and promoter sites, and simultaneously activate and repress pro-pluripotent and differentiation genes, respectively (Remenyi et al, 2003; Niwa, 2007). Interestingly, apart from maintaining the pluripotent identity, Oct4 expression levels have been shown to influence