Heterogeneous enhancer states orchestrate β cell responses to metabolic stress

Liu Wang, Jie Wu, Madeline Sramek, S. M. Bukola Obayomi, Peidong Gao, Yan Li, Aleksey V. Matveyenko and Zong Wei ()
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Liu Wang: Mayo Clinic College of Medicine
Jie Wu: Mayo Clinic College of Medicine
Madeline Sramek: Mayo Clinic College of Medicine
S. M. Bukola Obayomi: Mayo Clinic College of Medicine
Peidong Gao: Case Western Reserve University
Yan Li: Case Western Reserve University
Aleksey V. Matveyenko: Mayo Clinic College of Medicine
Zong Wei: Mayo Clinic College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53717-0

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