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.

A fundamental problem in human biology is to understand how portions of the genome get activated and de-activated in the different cell types that comprise the human body, and how defects of the molecular mechanisms controlling this process lead to human cancer. The work supported by the Schrödinger Fellowship led to a key discovery that the human genome is partitioned into thousands of loop structures that constrain the activity of gene regulatory elements to their appropriate target genes. These loops form three-dimensional neighborhoods around genes and are essential for proper gene activity. Mutations that perturb neighborhood organization can lead to the activation of cancer-causing oncogenes. Ultimately, these insights will enable the development of new cancer biomarkers, and create a framework to design strategies that interfere with specific chromosome structures as a therapeutic approach to disrupt oncogene activity in human neoplasms.