My goal as a genomic biologist is to improve our understanding of how glucose homeostasis is regulated by the pancreatic beta cell, and to suggest new avenues for treatment of diabetes. To this end, I have spent several years developing expertise in the use of high-throughput genomics technologies. In this proposal I will further train in beta-cell biology and pancreatic physiology in the Islet Transplant Center at the Joslin Diabetes Center under the sponsorship of Gordon Weir and Susan Bonner-Weir, and learn to use shRNA constructs in the laboratory of David Sabatini to investigate the functional relevance of in vivo binding data. Understanding of the network of transcriptional regulators that dictate the phenotype of a beta cell will be key to determining how this highly specialized tissue develops and is maintained. To date, attempts to address this question have been hampered by the tools available to investigate, on a genomic scale, the transcriptional regulatory interactions that direct cellular phenotype. While a number of beta-cell specific transcription factors have been identified, largely on the basis of their ability to bind to the insulin promoter, their functional characterization has been largely limited to their interaction with a small set of heavily investigated genes. Preliminary data identifying the genomic occupancy of HNF transcription factors in liver and pancreas strongly suggests that tissue-specific transcription factors can coordinate apparently disparate cellular functions via promoter binding. This proposal will test the hypothesis that the tissue specific transcription factors that bind the insulin promoter are also responsible for the transcriptional regulation of other key beta-cell processes, such as glucose metabolism, signal transduction, secretion, and beta-cell specific miRNAs. Thus, my specific aims are * to test if transcription factors that regulate insulin also occupy the promoters of other genes key to beta-cell function. * to test if the genes whose promoters are bound by insulin regulators are actively controlled by insulin regulators.
