Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Scottsdale, AZ, USA.
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Nat Commun. 2024 Oct 30;15(1):9361. doi: 10.1038/s41467-024-53717-0.
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 H3K4me1H3K27ac 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.
肥胖引起的β细胞功能障碍是 2 型糖尿病发病的原因之一。然而，阐明胰岛功能障碍在单细胞水平上的表观遗传机制仍然具有挑战性。在这里，我们对来自瘦鼠和肥胖鼠胰岛的单个核 RNA 以及增强子标记 H3K4me1 或 H3K27ac 进行了分析。我们的研究确定了与β细胞功能障碍轨迹相关的独特基因特征和增强子状态。有趣的是，虽然许多代谢应激诱导的基因在其增强子上表现出 H3K4me1 和 H3K27ac 的一致变化，但特定亚群的表达变化仅归因于 H3K4me1 或 H3K27ac 动力学的变化。值得注意的是，在瘦鼠β细胞中普遍存在且由 FoxA2 占据的一组 H3K4me1H3K27ac 启动的增强子在代谢应激后大部分缺失。最后，细胞间通讯分析确定神经生长因子（NGF）是β细胞的保护性旁分泌信号，通过抑制内质网应激来发挥作用。总之，我们的研究结果定义了单个β细胞对代谢挑战的异质增强子反应。
