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

• Shiqi Jia ^[1] ; Andranik Ivanov ^[1] ; Dinko Blasevic ^[1] ; Thomas Müller ^[1] ; Bettina Purfürst ^[2] ; Wei Sun ^[1] ; Wei Chen ^[1] ; Matthew N Poy ^[1] ; Nikolaus Rajewsky ^[1] ; Carmen Birchmeier ^[1]
  1. [1] Max Delbrück Center for Molecular Medicine

     Max Delbrück Center for Molecular Medicine

     Berlin, Stadt, Alemania

     
  2. [2] 3 Electron Microscopy Platform, Max-Delbrück-Center for Molecular Medicine Berlin, Germany
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 10, 2015, págs. 1417-1433
• Idioma: inglés
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• Resumen

  • 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.