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The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function

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 coregu...

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Autores principales: Spaeth, Jason M., Liu, Jin-Hua, Peters, Daniel, Guo, Min, Osipovich, Anna B., Mohammadi, Fardin, Roy, Nilotpal, Bhushan, Anil, Magnuson, Mark A., Hebrok, Matthias, Wright, Christopher V.E., Stein, Roland
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702633/
https://www.ncbi.nlm.nih.gov/pubmed/31201281
http://dx.doi.org/10.2337/db19-0349
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author Spaeth, Jason M.
Liu, Jin-Hua
Peters, Daniel
Guo, Min
Osipovich, Anna B.
Mohammadi, Fardin
Roy, Nilotpal
Bhushan, Anil
Magnuson, Mark A.
Hebrok, Matthias
Wright, Christopher V.E.
Stein, Roland
author_facet Spaeth, Jason M.
Liu, Jin-Hua
Peters, Daniel
Guo, Min
Osipovich, Anna B.
Mohammadi, Fardin
Roy, Nilotpal
Bhushan, Anil
Magnuson, Mark A.
Hebrok, Matthias
Wright, Christopher V.E.
Stein, Roland
author_sort Spaeth, Jason M.
collection PubMed
description 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.
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spelling pubmed-67026332020-09-01 The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function Spaeth, Jason M. Liu, Jin-Hua Peters, Daniel Guo, Min Osipovich, Anna B. Mohammadi, Fardin Roy, Nilotpal Bhushan, Anil Magnuson, Mark A. Hebrok, Matthias Wright, Christopher V.E. Stein, Roland Diabetes Islet Studies 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. American Diabetes Association 2019-09 2019-06-14 /pmc/articles/PMC6702633/ /pubmed/31201281 http://dx.doi.org/10.2337/db19-0349 Text en © 2019 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Islet Studies
Spaeth, Jason M.
Liu, Jin-Hua
Peters, Daniel
Guo, Min
Osipovich, Anna B.
Mohammadi, Fardin
Roy, Nilotpal
Bhushan, Anil
Magnuson, Mark A.
Hebrok, Matthias
Wright, Christopher V.E.
Stein, Roland
The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title_full The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title_fullStr The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title_full_unstemmed The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title_short The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function
title_sort pdx1-bound swi/snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β-cell function
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702633/
https://www.ncbi.nlm.nih.gov/pubmed/31201281
http://dx.doi.org/10.2337/db19-0349
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