Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding
Year: 2023
Type: article
Abstract: 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.
Source: Cell Death and Disease
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,490
Funders: U.S. Department of Health and Human Services, Villum Fonden, Juvenile Diabetes Research Foundation United Kingdom, Danish Diabetes Academy, European Foundation for the Study of Diabetes, Novo Nordisk, Augustinus Fonden, Faculty of Health and Medical Sciences, University of Western Australia, Novo Nordisk Fonden, Novo Nordisk Foundation Center for Basic Metabolic Research, Centro de Investigação em Biomedicina, National Institutes of Health, University of California, San Diego, Det Sundhedsvidenskabelige Fakultet, Københavns Universitet, VILLUM Center for Bioanalytical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Epigenetic strategies for the in vitro generation of replacement beta cells, G1462415530, G1796465521, G1964838885, G2142475802, G2208385882, G2560718436, Genetic Regulation of Adiposity and Associated CVD Risks, G417624449, G4305273984, G5862055050, G598865872, G6331392353, Novel insights into nutrient-dependent regulation of beta cell proliferation, Epigenetic determinants of beta cell development and function, G8603628221, G9000140433, Diabetes Research Center (DRC)
OpenAlex ID: W4383264322