Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice
| العنوان: | Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice |
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| المؤلفون: | Aline Daniel, Cassandra L. McDonald, Brad G. Hoffman, Nina Maeshima, Dan S. Luciani, Ben Vanderkruk, Daniel J. Pasula, Meilin An, Priya Suresh |
| المصدر: | Diabetologia. 66:1097-1115 |
| بيانات النشر: | Springer Science and Business Media LLC, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Methyltransferase, biology, Chemistry, Endocrinology, Diabetes and Metabolism, Promoter, Chromatin, Cell biology, Histone, Gene expression, biology.protein, Internal Medicine, Gene silencing, H3K4me3, Epigenetics |
| الوصف: | Aims/hypothesis Beta cells control glucose homeostasis via regulated production and secretion of insulin. This function arises from a highly specialised gene expression programme that is established during development and then sustained, with limited flexibility, in terminally differentiated cells. Dysregulation of this programme is seen in type 2 diabetes but mechanisms that preserve gene expression or underlie its dysregulation in mature cells are not well resolved. This study investigated whether methylation of histone H3 lysine 4 (H3K4), a marker of gene promoters with unresolved functional importance, is necessary for the maintenance of mature beta cell function. Methods Beta cell function, gene expression and chromatin modifications were analysed in conditional Dpy30 knockout mice, in which H3K4 methyltransferase activity is impaired, and in a mouse model of diabetes. Results H3K4 methylation maintains expression of genes that are important for insulin biosynthesis and glucose responsiveness. Deficient methylation of H3K4 leads to a less active and more repressed epigenome profile that locally correlates with gene expression deficits but does not globally reduce gene expression. Instead, developmentally regulated genes and genes in weakly active or suppressed states particularly rely on H3K4 methylation. We further show that H3K4 trimethylation (H3K4me3) is reorganised in islets from the Leprdb/db mouse model of diabetes in favour of weakly active and disallowed genes at the expense of terminal beta cell markers with broad H3K4me3 peaks. Conclusions/interpretation Sustained methylation of H3K4 is critical for the maintenance of beta cell function. Redistribution of H3K4me3 is linked to gene expression changes that are implicated in diabetes pathology. Graphical abstract |
| تدمد: | 1432-0428 0012-186X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a743a6f3475ec9f8172e2c49f228f996 https://doi.org/10.1007/s00125-023-05896-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a743a6f3475ec9f8172e2c49f228f996 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14320428 0012186X |
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