A set of Sox2-dependent OSN enhancers mediates the immediate response to neural induction and default neural differentiation of embryonic stem cells

Sox2 is a transcription factor involved in the regulatory network maintaining the pluripotency of embryonic stem cells in culture as well as in early embryos. In addition, Sox2 plays a pivotal role in neural stem cell formation and neurogenesis. How Sox2 can serve both processes has remained elusive. Here we identified a set of Sox2-dependent neural associated enhancers (SONAE) activated immediately following neural induction and required in neural gene activation. SONAE are a distinct subgroup (1898) of 8531 Oct4/Sox2/Nanog (OSN) bound enhancers, characterized by enhanced Sox2 binding and chromatin accessibility. SONAE activation is triggered by neural induction via Retinoic Acid treatment of wild type cells and is antagonized by mesodermal transcription factors repressing Sox2 following mesoderm induction. Neural differentiation is also set off by default in Smad4 ablated cells resistant to mesodermal induction. Our data provide mechanistic insight into the regulation of early neural versus mesodermal induction in ESCs and embryos.