# Control of islet beta specific pdx-1 and mafA transcription

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $388,176

## Abstract

The Pancreas Duodenum Homeobox-1 protein (Pdx1) is one of the most important transcriptional
regulators in the pancreas, since it plays a fundamental role in the early formation of all pancreatic cell types
and in the production and function of adult islet β cells. Moreover, inactivation of human Pdx1 contributes to
diabetic islet β cell dysfunction. Gene regulation by transcription factors (TFs) like Pdx1 necessitates the
recruitment through protein-protein interactions of coregulators, which confer a second level of specificity to
the transcriptional response due to their positive and/or negative actions. Because little was known about the
coregulators recruited by islet-enriched TFs, a principal objective during the prior funding cycle was to isolate
coregulators of Pdx1 from mouse β cells. While many were identified, we focused on determining the
significance to Pdx1 of the Swi/Snf chromatin remodeling complex. Our studies not only strongly suggest
that Swi/Snf is a critical regulator in β cell lines, but that recruitment to Pdx1 is compromised under the
dysfunctional conditions associated with human Type 2 diabetes. A major objective in this proposal will be to
determine the in vivo significance of Pdx1:Swi/Snf control in the developing pancreas and islet β cells
postnatally, with preliminary results supporting a prominent role. Because Swi/Snf does not have as powerful
a regulatory impact as Pdx1, we will also work towards defining the underlying transcriptional mechanisms of
other Pdx1 recruited coregulators on islet β cell activity.
 Our earlier transgenic- and cell line-based experiments localized pancreatic cell-type-specific
transcriptional regulatory areas of the Pdx1 gene to conserved 5'-flanking region sequences. We have
constructed deletion mutants in the Area IV (base pair (bp) -6200/-5670) and Area II (bp -2153/-1923) control
regions of the endogenous mouse Pdx1 gene to analyze the individual contributions of these enhancers to
pancreatic cell type specification, differentiation, and function in vivo. Strikingly, the molecular and
physiological impact of the Pdx1ΔArea IV mutant was almost exclusively during the postnatal weaning period.
Another principal focus will be on determining if islet β cell dysfunction in this mutant disrupts the activity of
the circadian clock, as the mediating CLOCK and BMAL1 TFs reside within Pdx1 bound transcriptionally
active enhancers and yield a similar in vivo TF mutant phenotype to Pdx1ΔArea IV. Collectively, our studies will
focus on defining mechanisms used by Pdx1 in controlling the normal formation and activity of islet β cells,
and determining their possible contribution in the pathogenesis of diabetes. These findings will have a
significant positive impact by providing knowledge relevant to those developing diagnostic and therapeutic
approaches for disease treatment.

## Key facts

- **NIH application ID:** 9932368
- **Project number:** 5R01DK050203-22
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Joseph Bass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,176
- **Award type:** 5
- **Project period:** 1995-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932368

## Citation

> US National Institutes of Health, RePORTER application 9932368, Control of islet beta specific pdx-1 and mafA transcription (5R01DK050203-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932368. Licensed CC0.

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