Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding
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Insufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from individuals with diabetes and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4, Hes-1, and Hey-1 which are transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism by which BMP-2 induces beta cell dysfunction and loss of cell maturity. Mouse islets exposed to BMP-2 for 10 days showed impaired glucose-stimulated insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of cell maturity and proliferation markers specific to the beta cell such as Ins1, Ucn3, and Ki67 and increased expression of Id1-4, Hes-1, and Hey-1. The top 30 most regulated proteins significantly correlated with corresponding mRNA expression. BMP-2-induced gene expression changes were associated with a predominant reduction in acetylation of H3K27 and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2 induces loss of beta cell maturity and suggest that remodeling of H3K27ac and decreased NeuroD1 DNA binding activity participate in the effect of BMP-2 on beta cell dysfunction.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 399 |
| Tidsskrift | Cell Death and Disease |
| Vol/bind | 14 |
| Udgave nummer | 7 |
| Antal sider | 16 |
| ISSN | 2041-4889 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank Helle Fjordvang, Department of Biomedical Sciences, University of Copenhagen for her expert technical assistance. Further, we acknowledge the Core Facility for Integrated Microscopy (CFIM), Faculty of Health and Medical Sciences, University of Copenhagen. We acknowledge the support of the UCSD IGM Genomic Center (supported by P30 DK064391) for library preparation and sequencing. We acknowledge the Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical and computational expertise and support.
Funding Information:
We thank Helle Fjordvang, Department of Biomedical Sciences, University of Copenhagen for her expert technical assistance. Further, we acknowledge the Core Facility for Integrated Microscopy (CFIM), Faculty of Health and Medical Sciences, University of Copenhagen. We acknowledge the support of the UCSD IGM Genomic Center (supported by P30 DK064391) for library preparation and sequencing. We acknowledge the Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical and computational expertise and support.
Funding Information:
This work was supported by Novo Nordisk Foundation through the Danish Diabetes Academy (GLC and MP), European Foundation for the Study of Diabetes (Program in cellular plasticity underlying the pathophysiology of type 2 diabetes), Augustinus Fonden (GLC), Juvenile Diabetes Research Foundation grant 3-PDF-2014- 193-A-N (MW), a Diabetes Research Center Pilot and Feasibility grant P30 DK063491 (MW), US Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK068471 (MW), R01 DK078803 and U01 DK089567 (MS), VILLUM Center for Bioanalytical Sciences (VILLUM Foundation grant no. 7292), by PRO-MS, Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B).
Publisher Copyright:
© 2023, The Author(s).
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