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UBC Theses and Dissertations

Unraveling the molecular physiology of the β-cell: genome wide analysis of binding sites for the transcription factor PDX1 Beach, Michael


The selected expression of the genome determines distinct cell types, properties, and conditions. In the pancreatic β-cell, our knowledge of how this is regulated and maintained is incomplete. Deciphering the molecular physiology of the β-cell is critical to develop improvements for expanding pools of donor islets for transplantation, the most promising curative option for sufferers of diabetes. Genomic regulation is controlled primarily by transcription factors, of which pancreatic duodenal homeobox 1 (Pdxl) plays a critical role in both the developing and mature pancreas. As such, I begin to unlock the molecular physiology of the β-cell by identifying the binding sites of Pdxl in pancreatic islets on a genome-wide scale through the use of chromatin immunoprecipitation followed by sequencing (ChIP-Seq). This provides the best picture of Pdxl binding that has ever been assembled. Moreover, I identify a highly co-occurring relationship between Pdxl and pre-B-cell leukemia homeobox 1 (Pbxl) in adult islets. The coupling of this data with other genome-wide analyses will prove invaluable to discovering novel transcriptional complexes and the genes they regulate. It will also contribute to the creation of an islet transcriptional network, thereby greatly enhancing our knowledge of β-cell regulation.

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