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- Title
The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function.
- Authors
Spaeth, Jason M.; Jin-Hua Liu; Peters, Daniel; Min Guo; Osipovich, Anna B.; Mohammadi, Fardin; Roy, Nilotpal; Bhushan, Anil; Magnuson, Mark A.; Hebrok, Matthias; Wright, Christopher V. E.; Stein, Roland; Liu, Jin-Hua; Guo, Min
- Abstract
Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β-cells lost the ability to produce the mRNAs for Ins and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the Ins gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas, and we discuss how disrupting their association could influence type 1 and type 2 diabetes susceptibility.
- Subjects
PROGENITOR cells; CELL proliferation; CHROMATIN; ISLANDS of Langerhans; TRANSCRIPTION factors; GASTRIC inhibitory polypeptide
- Publication
Diabetes, 2019, Vol 68, Issue 9, p1806
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0349