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EMBO J. 2015 May 12;34(10):1417-33. doi: 10.15252/embj.201490819. Epub 2015 Mar 31.

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

Author information

1
Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany cbirch@mdc-berlin.de jshiqi@mdc-berlin.de.
2
Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
3
Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
4
Electron Microscopy Platform, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
5
Scientific Genomics Platform, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
6
Molecular Mechanisms of Metabolic Disease, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

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.

KEYWORDS:

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

PMID:
25828096
PMCID:
PMC4492000
DOI:
10.15252/embj.201490819
[Indexed for MEDLINE]
Free PMC Article

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