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

Shiqi Jia, Andranik Ivanov, Dinko Blasevic, Thomas Müller, Bettina Purfürst, Wei Sun, Wei Chen, Matthew N. Poy, Nikolaus Rajewsky, Carmen Birchmeier

Research output: Contribution to journalArticlepeer-review

Abstract

Key transcription factors control the gene expression program in mature pancreatic β-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 β-cells. We used Insm1 ablation in mature β-cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1-dependent genes identified previously in developing β-cells markedly differ from the ones identified in the adult. In particular, adult mutant β-cells resemble immature β-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 β-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 β-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in β-cells, and disruption of this network results in functional failure.

Original languageEnglish (US)
Pages (from-to)1417-1433
Number of pages17
JournalEMBO Journal
Volume34
Issue number10
DOIs
StatePublished - May 12 2015
Externally publishedYes

Keywords

  • Insm1
  • development
  • differentiation
  • maturation
  • metabolisms
  • pancreatic beta cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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