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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK050203-17
Application #
8663880
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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