Heterogeneous enhancer states orchestrate β cell responses to metabolic stress

作者：Liu Wang, Jie Wu, Madeline Sramek, S. M. Bukola Obayomi, Peidong Gao, Yan Li, Aleksey V. Matveyenko, Zong Wei · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-53717-0 · 被引用次数：10 · 研究领域：Pancreatic function and diabetes、Diabetes and associated disorders、Diet, Metabolism, and Disease

Obesity-induced β cell dysfunction contributes to the onset of type 2 diabetes. Nevertheless, elucidating epigenetic mechanisms underlying islet dysfunction at single cell level remains challenging. Here we profile single-nuclei RNA along with enhancer marks H3K4me1 or H3K27ac in islets from lean or obese mice. Our study identifies distinct gene signatures and enhancer states correlating with β cell dysfunction trajectory. Intriguingly, while many metabolic stress-induced genes exhibit concordant changes in both H3K4me1 and H3K27ac at their enhancers, expression changes of specific subsets are solely attributable to either H3K4me1 or H3K27ac dynamics. Remarkably, a subset of H3K4me1+H3K27ac- primed enhancers prevalent in lean β cells and occupied by FoxA2 are largely absent after metabolic stress. Lastly, cell-cell communication analysis identified the nerve growth factor (NGF) as protective paracrine signaling for β cells through repressing ER stress. In summary, our findings define the heterogeneous enhancer responses to metabolic challenges in individual β cells. β cell dysfunction contributes to the onset of type 2 diabetes. Here the authors profile single-nuclei RNA along with enhancer marks H3K4me1 or H3K27ac in islets and suggest highly heterogeneous enhancer states in response to metabolic challenges.