Epigenetic regulation by TOR signaling

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DESCRIPTION (provided by applicant): Precise control of cell growth and proliferation in response to nutrient availability is essential for human health. Aberrant regulation of nutrient sensing pathways, either through elevated nutrient availability or genetic mutation, can lead to inappropriate cell growth or proliferation and cause diseases such as cancer. One critical aspect of nutrient signaling is the regulation of a cell's gene expression program. How cells transmit nutrient information to the machinery regulating gene expression is still poorly understood, however. Because DNA is packaged into chromatin, which consists of DNA in a complex with histone proteins, nutrient signaling must regulate chromatin structure to elicit the epigenetic changes necessary to alter gene expression. The studies outlined in this proposal will make use of the budding yeast model system to understand how a critical nutrient signaling cascade, the target of rapamycin (TOR) pathway, regulates epigenetic processes to control gene transcription. Aim I of this project will utilize yeast genetic, molecular biology, and biochemical approaches to delineate how TOR signaling regulates a histone chaperone complex to control RNA polymerase I transcription of ribosomal DNA. Aim II will use a chemical genomics-based approach to find TOR-regulated epigenetic pathways by screening a histone H3 and H4 mutant library in the presence of the TOR inhibitor rapamycin. These mutants will then be combined with mutations in the TOR pathway to further characterize their genetic interactions. In combination, these studies will delineate a novel epigenetic pathway important for RNA polymerase I transcription and will serve to identify new, TOR-regulated epigenetic pathways critical for nutrient regulated cell growth. PUBLIC HEALTH RELEVANCE: The project's goal is to identify how cells transmit nutrient signals to the epigenetic machinery to regulate gene expression critical for cell growth. Because nutrient signaling pathways are aberrantly regulated in cancer, understanding how they control epigenetic processes will lead to the identification of new anti-cancer drug targets.