Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A

Author(s): Weng, C; Gu, A; Zhang, S; Lu, L; Ke, L; Gao, P; Liu, X; Wang, Y; Hu, P; Plummer, D; MacDonald, E; Zhang, S; Xi, J; Lai, S; Leskov, K; Yuan, K; Jin, F; Li, Y;
Year: 2023;  
Journal: Nature Communications;  
Volume: 14;  
Issue: 1;  

Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D.