Transcriptional regulatory networks in embryonic stem cells.

Transcriptional regulation is one of the most fundamental processes in biology, governing the morphology, function, and behavior of cells and thus the survival of organisms. The embryonic stem cell (ESC) provides a good model for the understanding of transcriptional regulation in vertebrate systems. Recent efforts have led to the identification of molecular events, which confer upon these cells the unique properties of pluripotency and self renewal. The core regulatory network maintaining the ESC identity involves three master regulators: Oct4, Sox2, and Nanog. Large-scale mapping studies interrogating the binding sites of these and other transcription factors showed co-occupancy of distinct sets of transcription factors. The assembly of multitranscription factor complexes could serve as a mechanism for providing specificity in regulating ESC-specific gene expression. These studies are also beginning to unravel the transcriptional regulatory networks that govern the ESC identity. Loss-of-function RNAi screens also identified novel regulatory molecules involved in the stable propagation of the ESC state. This argues for an ESC transcriptional regulation program in which interconnected transcriptional regulatory networks involving large numbers of transcription factors and epigenetic modifiers work in concert on ESC- and differentiation-specific genes to achieve cell state stability. This chapter traces the major efforts made over the past decade in dissecting the transcriptional regulatory network governing ESC identity and offers perspectives on the future directions of the field.