期刊
DIABETES
卷 68, 期 9, 页码 1806-1818出版社
AMER DIABETES ASSOC
DOI: 10.2337/db19-0349
关键词
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资金
- American Diabetes Association [1-16-PDF-109]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [K01-DK-115633, R01-DK-050203]
- National Cancer Institute [R01-CA-172045]
- Vanderbilt Flow Cytometry Shared Resource (National Cancer Institute) [P30-CA-68485]
- Clinical and Translational Science Awards [5UL1-RR-024975-03]
- Vanderbilt Ingram Cancer Center (National Cancer Institute) [P30-CA-68485]
- Vanderbilt Vision Center (National Eye Institute) [P30-EY-08126]
- National Institutes of Health/National Center for Research Resources [G20-RR-030956]
- Vanderbilt Hormone Assay and Analytical Services Core (National Institute of Diabetes and Digestive and Kidney Diseases) [DK-020593]
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 beta-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 beta-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient beta-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.
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