The Pdx1-bound Swi/Snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β-cell function

Jason M. Spaeth, Jin Hua Liu, Daniel Peters, Min Guo, Anna B. Osipovich, Fardin Mohammadi, Nilotpal Roy, Anil Bhushan, Mark A. Magnuson, Matthias Hebrok, Christopher V.E. Wright, Roland Stein

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 diabeteslinked 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 isletenriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the Ins gene enhancer, demonstrating the importance of this association inmediating 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.

Original languageEnglish
Pages (from-to)1806-1818
Number of pages13
JournalDiabetes
Volume68
Issue number9
DOIs
StatePublished - 1 Sep 2019
Externally publishedYes

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