The pancreatic duodenal homeobox 1 (Pdx1) gene encodes a transcription factor (TF) that is essential in early pancreas development and later in the formation, maintenance and activity of islet ?-cells. We have shown that Pdx1 transcription in pancreatic progenitors and differentiated ?-cells is driven by conserved 5'-flanking sequences defined by Areas I, II, III and IV, and that complete deletion of Areas I-II-III in mice causes severe pancreas hypoplasia, similar to the global Pdx1 gene knockout. We have strong evidence that mammal-specific Area II is the functional core of this region. The epigenetic architecture of Area II will be compared to control regions in genes that are directly regulated by the Pdx1 protein. Area II is predicted to contain a poised epigenetic architecture in embryonic progenitors that produce little Pdx1 (termed Pdx1LO), which is subsequently modified as a prerequisite to high Pdx1 (Pdx1HI) production required for ?-cell formation, differentiation and mature cell function. Moreover, we will determine how newly identified positive- and negative-acting Area II TFs impact ?-cells. Strikingly, while transcriptional and chromatin-modifying networks are critical for functional ?-cell production, it is unclear how these networks interact, and specifically what coregulators are recruited to remodel chromatin within the pancreas. We will test the hypothesis that our newly identified coregulators of Pdx1 profoundly influence Pdx1-mediated gene control. These findings will provide valuable insight into the transcriptional regulatory mechanisms that will be effective in the production of cellular therapeutics for diabetes treatment, for example by forward directed differentiation or reprogramming.
Several candidate and genome-wide studies have identified risk loci for type 2 diabetes;these genes include many transcription factors implicated in the control of ?-cell development and function. Strikingly, the Pdx1 transcription factor is the only maturity onset diabetes of the young gene in which homozygous mutant humans have pancreatic agenesis, while heterozygotes develop early-onset diabetes due to islet ?-cell dysfunction. Our proposed studies are designed to define the underlying transcriptional mechanisms through which Pdx1 and its associated coregulators influence ?-cell maturation and adult cell function. We believe that our findings will be essential to the ongoing efforts to generate ?-cells from ES, iPS and/or adult cell sources for type 1 diabetes treatment.
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|Yang, Yu-Ping; Magnuson, Mark A; Stein, Roland et al. (2017) The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal ?-cell maturation. Development 144:248-257|
|Hunter, Chad S; Stein, Roland W (2017) Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet ?-Cells in Type 2 Diabetes. Front Genet 8:35|
|Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70|
|Spaeth, J M; Walker, E M; Stein, R (2016) Impact of Pdx1-associated chromatin modifiers on islet ?-cells. Diabetes Obes Metab 18 Suppl 1:123-7|
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