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

Author

Listed:
  • Chen Weng

    (Case Western Reserve University
    Case Western Reserve University)

  • Anniya Gu

    (Case Western Reserve University
    Case Western Reserve University)

  • Shanshan Zhang

    (Case Western Reserve University
    Case Western Reserve University)

  • Leina Lu

    (Case Western Reserve University)

  • Luxin Ke

    (Case Western Reserve University
    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
    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
    Case Western Reserve University)

  • Konstantin Leskov

    (Case Western Reserve University)

  • Kyle Yuan

    (Case Western Reserve University
    Case Western Reserve University)

  • Fulai Jin

    (Case Western Reserve University
    Case Western Reserve University
    Case Western Reserve University
    Case Western Reserve University)

  • Yan Li

    (Case Western Reserve University)

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.

Suggested Citation

  • 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 & Konstant, 2023. "Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41228-3
    DOI: 10.1038/s41467-023-41228-3
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    References listed on IDEAS

    as
    1. Elizabeth Haythorne & Maria Rohm & Martijn Bunt & Melissa F. Brereton & Andrei I. Tarasov & Thomas S. Blacker & Gregor Sachse & Mariana Silva dos Santos & Raul Terron Exposito & Simon Davis & Otto Bab, 2019. "Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Craig Dorrell & Jonathan Schug & Pamela S. Canaday & Holger A. Russ & Branden D. Tarlow & Maria T. Grompe & Tamara Horton & Matthias Hebrok & Philip R. Streeter & Klaus H. Kaestner & Markus Grompe, 2016. "Human islets contain four distinct subtypes of β cells," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    3. Stuart B. Smith & Hui-Qi Qu & Nadine Taleb & Nina Y. Kishimoto & David W. Scheel & Yang Lu & Ann-Marie Patch & Rosemary Grabs & Juehu Wang & Francis C. Lynn & Takeshi Miyatsuka & John Mitchell & Rina , 2010. "Rfx6 directs islet formation and insulin production in mice and humans," Nature, Nature, vol. 463(7282), pages 775-780, February.
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