[Show abstract][Hide abstract] ABSTRACT: Author Summary
Embryonic stem cells have the unique and defining property of pluripotency: the ability to differentiate into all cell types. Key transcription factors form interconnected gene regulatory networks that control pluripotency and differentiation. Recently, the transcriptional repressor RE1-silencing transcription factor (REST) was implicated in the maintenance of pluripotency. This was surprising, given that REST has long been known as an essential regulator of neurodevelopment. How does REST regulate pluripotency? Does REST have distinct cohorts of binding sites and target genes in different developmental contexts? To address these questions, we made whole-genome maps of REST binding sites in two mouse stem cell types: embryonic (ESC) and neural (NSC) stem cells. These data were compared with each other and with gene expression data from cells in which REST activity was inhibited. The target genes were almost completely distinct in the two cell types. Surprisingly, we found that REST recruitment has two approximately equal components: common sites across all cells and an ESC-specific component. These pluripotency-associated sites are enriched for particular classes of genes, including those mediating the Wnt signaling pathway, which is an essential regulator of pluripotency.