title: Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function.
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.
authors.affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany cbirch@mdc-berlin.de jshiqi@mdc-berlin.de.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Jia
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Andranik
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Dinko
authors.initials: D
authors.lastname: Blasevic
authors.affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Electron Microscopy Platform, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Purfürst
authors.affiliation: Scientific Genomics Platform, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Scientific Genomics Platform, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Molecular Mechanisms of Metabolic Disease, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Poy
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Developmental Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany cbirch@mdc-berlin.de jshiqi@mdc-berlin.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D012097:Repressor Proteins; D014157:Transcription Factors; C496503:Foxa2 protein, mouse; C477059:Insm1 protein, mouse; C501008:Neurod1 protein, mouse
keywords: Insm1; development; differentiation; maturation; metabolisms; pancreatic beta cells
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