Heterogeneous enhancer states orchestrate β cell responses to metabolic stress

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...

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Veröffentlicht in:Nature communications 2024-10, Vol.15 (1), p.9361-19, Article 9361
Hauptverfasser: Wang, Liu, Wu, Jie, Sramek, Madeline, Obayomi, S. M. Bukola, Gao, Peidong, Li, Yan, Matveyenko, Aleksey V., Wei, Zong
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Sprache:eng
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Zusammenfassung: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-53717-0