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Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function

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Item Type:Article
Title:Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function
Creators Name:Jia, S. and Ivanov, A. and Blasevic, D. and Müller, T. and Purfürst, B. and Sun, W. and Chen, W. and Poy, M.N. and Rajewsky, N. and Birchmeier, C.
Abstract:Key transcription factors control the gene expression program in mature pancreatic {beta}-cells, but their integration into regulatory networks is little understood. Here, we show that Insm1, Neurod1 and Foxa2 directly interact and together bind regulatory sequences in the genome of mature pancreatic {beta}-cells. We used Insm1 ablation in mature {beta}-cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1-dependent genes identified previously in developing {beta}-cells markedly differ from the ones identified in the adult. In particular, adult mutant {beta}-cells resemble immature {beta}-cells of newborn mice in gene expression and functional properties. We defined Insm1, Neurod1 and Foxa2 binding sites associated with genes deregulated in Insm1 mutant {beta}-cells. Remarkably, combinatorial binding of Insm1, Neurod1 and Foxa2 but not binding of Insm1 alone explained a significant fraction of gene expression changes. Human genomic sequences corresponding to the murine sites occupied by Insm1/Neurod1/Foxa2 were enriched in single nucleotide polymorphisms associated with glycolytic traits. Thus, our data explain part of the mechanisms by which {beta}-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in {beta}-cells, and disruption of this network results in functional failure.
Keywords:Development, Differentiation, Insm1, Maturation, Metabolisms, Pancreatic beta Cells, Animals, Mice
Source:EMBO Journal
Publisher:EMBO Press / Wiley
Page Range:1417-1433
Date:12 May 2015
Official Publication:https://doi.org/10.15252/embj.201490819
PubMed:View item in PubMed

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