Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.
EMBO J, 2015/5/12;34(10):1417-33.
Jia S[1], Ivanov A[2], Blasevic D[3], Müller T[3], Purfürst B[4], Sun W[5], Chen W[5], Poy MN[6], Rajewsky N[2], Birchmeier C[1]
Affiliations
PMID: 25828096DOI: 10.15252/embj.201490819
Impact factor: 14.012
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
MeSH terms
Animals; Basic Helix-Loop-Helix Transcription Factors; DNA-Binding Proteins; Genotype; Hepatocyte Nuclear Factor 3-beta; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Protein Binding; Repressor Proteins; Transcription Factors
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