folder

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

Authors

  • S. Jia
  • A. Ivanov
  • D. Blasevic
  • T. Müller
  • B. Purfürst
  • W. Sun
  • W. Chen
  • M.N. Poy
  • N. Rajewsky
  • C. Birchmeier

Journal

  • EMBO Journal

Citation

  • EMBO J 34 (10): 1417-1433

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.


DOI

doi:10.15252/embj.201490819