Sox2 co-occupies distal enhancer elements with cell-type-specific POU factors to specify cell identity in embryonic stem cells and neural precursor cells

Abstract

Sox2 is a master regulator of two distinct cellular states, that of pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs), but what common or distinct roles Sox2 may play in these cell types not fully understood. Further, the molecular mechanisms by which Sox2 can specify two distinct cell identities are as of yet unclear. This thesis is aimed at answering these fundamental questions. In ESCs, Sox2 was associated with a subset of poised regulators of nervous system development, and upon differentiation into NPCs Sox2 selectively activates those which are important for progenitor cell state, while keeping others poised to become activated in later neural development. These data suggested that Sox2 might act as a pioneer factor for neural development throughout embryogenesis. While Sox2 is known to co-occupy target loci in ESCs with the POU factor Oct4, in NPCs Sox2 interacts with the central-nervous-system-expressed POU factors Brn1 and Brn2. By utilizing distinct composite Sox:Octamer motifs in each cell type, Sox2:POU modules control the expression of thousands of genes involved in the development of the neural lineage in a cell-type-specific manner. These data advance our understanding of the mechanism by which transcription factors control cell fate transitions, and indicate that combinatorial interactions between transcription factors may be a pervasive mechanism of transcriptional control in development