We propose to begin mapping the transcriptional regulatory circuitry that controls the gene expression programs of embryonic stem cells and selected differentiated cells. A short-term goal of this study is to learn how the regulatory circuitry of embryonic stem cells contributes to pluripotency, and a long-term goal is to use knowledge of this circuitry to facilitate efforts to manipulate cellular fates. Mapping transcriptional regulatory circuitry can be initiated by identifying the active and silent portions of the genome and determining how master regulators control a core set of genes. These cell-type specific maps will define active and repressed chromatin structure for the entire non-repeat genome and identify the core regulatory circuitry that defines cellular phenotype. To accomplish this, the specific aims of the proposal are: 1) further develop experimental and analytical technologies that identify the genome-wide location of proteins associated with vertebrate genomes in vivo, 2) define the active and repressed chromatin structure for the entire non-repeat genome in human embryonic stem cells and compare it to that of two differentiated cell types, 3) determine how master regulators contribute to the core transcriptional regulatory circuitry of human embryonic stem cells and two differentiated cells, and 4) identify conserved components of the epigenetic state and core transcriptional regulatory circuitry in human and mouse cells to facilitate genetic tests and help identify the key controls of cell state. Improved understanding of vertebrate chromatin structure and transcriptional circuitry from these studies should lead to new insights into embryonic stem cell pluripotency, will generate maps of regulatory circuitry that may facilitate efforts to manipulate cell fates for regenerative medicine, and will provide the foundation for further mapping regulatory circuitry in human and other vertebrate cells. ? ? ?
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