Heterogeneous enhancer states orchestrate β cell responses to metabolic stress

Obesity-induced β cell dysfunction is a significant contributor to the onset of type 2 diabetes. Metabolic stress triggers expansive enhancer and gene expression dynamics in islet endocrine cells. However, identifying the precise gene regulatory network and the corresponding epigenetic mechanisms driving the islet dysfunction remains challenging. Here we utilize Paired-Tag, a combinatorial index-based multi-omic platform, to concurrently profile single-nuclei RNA with H3K4me1 or H3K27ac, two distinct histone modifications defining enhancer states, in lean and obese islets. Our study revealed gene expression, distinct enhancer states, RNA-enhancer links, and intra-islet paracrine communications that align with amplified unfolded protein responses and decreased insulin secretion function at a single-cell level.