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| Item Type: | Article |
|---|---|
| Title: | Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β-cell function |
| Creators: |
Jia, S.  ORCID: https://orcid.org/0000-0001-8595-9314, Ivanov, A. ORCID: https://orcid.org/0000-0002-4824-1925, Blasevic, D., Müller, T. ORCID: https://orcid.org/0000-0001-8096-1853, Purfürst, B. ORCID: https://orcid.org/0000-0002-9887-7577, Sun, W. ORCID: https://orcid.org/0000-0001-9607-1361, Chen, W. ORCID: https://orcid.org/0000-0003-3263-1627, Poy, M.N. ORCID: https://orcid.org/0000-0002-4904-2426, Rajewsky, N. ORCID: https://orcid.org/0000-0002-4785-4332 and Birchmeier, C. ORCID: https://orcid.org/0000-0002-2041-8872
|
| Abstract: | Key transcription factors control the gene expression program in mature pancreatic {beta}-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 {beta}-cells. We used Insm1 ablation in mature {beta}-cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1-dependent genes identified previously in developing {beta}-cells markedly differ from the ones identified in the adult. In particular, adult mutant {beta}-cells resemble immature {beta}-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 {beta}-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 {beta}-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in {beta}-cells, and disruption of this network results in functional failure. |
| Keywords: | Development, Differentiation, Insm1, Maturation, Metabolisms, Pancreatic beta Cells, Animals, Mice |
| Source: | EMBO Journal |
| ISSN: | 0261-4189 |
| Publisher: | EMBO Press / Wiley |
| Volume: | 34 |
| Number: | 10 |
| Page Range: | 1417-1433 |
| Date: | 12 May 2015 |
| Official Publication: | https://doi.org/10.15252/embj.201490819 |
| PubMed: | View item in PubMed |
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