Role of Super-enhancers in Stem Cell Differentiation

Cell type-specific gene expression programs establish the identities of thousands of cell types that comprise the mammalian body. Mammalian development occurs through precisely executed transitions between gene expression programs that define cellular identities, and misregulation of these processes is the underlying cause of many forms of human disease. It has recently been reported that genes critical for cell identity are controlled by specialized gene regulatory elements, termed super-enhancers. Super-enhancers differ from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation. Though super-enhancers are found in many different cell types, how disassembly and formation of cell type-specific super- enhancers contribute to mammalian development is as yet unexplored. We propose to investigate with a combination of biochemical and molecular biology tools how super-enhancers are disassembled when embryonic stem cells differentiate, how new super-enhancers are established in differentiated lineages, and how these changes control the transition in the gene expression programs of the differentiating cells. Understanding this process would provide essential insights into how mammalian development is controlled, and how misregulation of gene expression programs contribute to developmental defects and human disease.

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