biostudies-literatureWang LU.S. Department of Health & Human Services | NIH | National Center for Advancing Translational SciencesNCATS NIH HHSRoubos Family Fund in Research, Mayo Nutrition and Obesity Research programNIDDK NIH HHSNHGRI NIH HHSNCI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases9361https://www.ebi.ac.uk/biostudies/studies/S-EPMC11522703biostudies-literatureUnknown15(1)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 Nature communicationsHeterogeneous enhancer states orchestrate β cell responses to metabolic stress.PMC11522703R01 DK098468R01 DK131437UL1 TR002377R01 CA267872R01 HG012384K01 DK120808R01 DK132651R01 DK113185Obayomi SMBWu JLi YSramek MGao PMatveyenko AVWei ZWang LfalseHeterogeneous 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 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 2024-01-01T00:00:00Z2024 Oct2026-07-16T03:08:31.391Z2025-04-04T02:34:21.03ZS-EPMC115227033947243410.1038/s41467-024-53717-0