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

Chen Weng, Anniya Gu, Shanshan Zhang, Leina Lu, Luxin Ke, Peidong Gao, Xiaoxiao Liu, Yuntong Wang, Peinan Hu, Dylan Plummer, Elise MacDonald, Saixian Zhang, Jiajia Xi, Sisi Lai, Konstantin Leskov, Kyle Yuan, Fulai Jin () and Yan Li ()
Additional contact information
Chen Weng: Case Western Reserve University
Anniya Gu: Case Western Reserve University
Shanshan Zhang: Case Western Reserve University
Leina Lu: Case Western Reserve University
Luxin Ke: Case Western Reserve University
Peidong Gao: Case Western Reserve University
Xiaoxiao Liu: Case Western Reserve University
Yuntong Wang: Case Western Reserve University
Peinan Hu: Case Western Reserve University
Dylan Plummer: Case Western Reserve University
Elise MacDonald: Case Western Reserve University
Saixian Zhang: Case Western Reserve University
Jiajia Xi: Case Western Reserve University
Sisi Lai: Case Western Reserve University
Konstantin Leskov: Case Western Reserve University
Kyle Yuan: Case Western Reserve University
Fulai Jin: Case Western Reserve University
Yan Li: Case Western Reserve University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41228-3

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