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A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA

Author

Listed:
  • Yinglei Li

    (Wuhan University)

  • Ran Zheng

    (Wuhan University)

  • Lai Jiang

    (Wuhan University)

  • Chenchao Yan

    (Wuhan University)

  • Ran Liu

    (Wuhan University)

  • Luyi Chen

    (Wuhan University)

  • Wenwen Jin

    (Wuhan University)

  • Yuanyuan Luo

    (Wuhan University)

  • Xiafei Zhang

    (Wuhan University)

  • Jun Tang

    (Zhongnan Hospital of Wuhan University)

  • Zhe Dai

    (Zhongnan Hospital of Wuhan University)

  • Wei Jiang

    (Wuhan University
    Human Genetics Resource Preservation Center of Wuhan University
    Hubei Provincial Key Laboratory of Developmentally Originated Disease)

Abstract

Human genetics analysis has identified many noncoding SNPs associated with diabetic traits, but whether and how these variants contribute to diabetes is largely unknown. Here, we focus on a noncoding variant, rs6048205, and report that the risk-G variant impairs the generation of PDX1+/NKX6-1+ pancreatic progenitor cells and further results in the abnormal decrease of functional β cells during pancreatic differentiation. Mechanistically, this risk-G variant greatly enhances RXRA binding and over-activates FOXA2 transcription, specifically in the pancreatic progenitor stage, which in turn represses NKX6-1 expression. Consistently, inducible FOXA2 overexpression could phenocopy the differentiation defect. More importantly, mice carrying risk-G exhibit abnormal pancreatic islet architecture and are more sensitive to streptozotocin or a high-fat diet to develop into diabetes eventually. This study not only identifies a causal noncoding variant in diabetes susceptibility but also dissects the underlying gain-of-function mechanism by recruiting stage-specific factors.

Suggested Citation

  • Yinglei Li & Ran Zheng & Lai Jiang & Chenchao Yan & Ran Liu & Luyi Chen & Wenwen Jin & Yuanyuan Luo & Xiafei Zhang & Jun Tang & Zhe Dai & Wei Jiang, 2024. "A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54151-y
    DOI: 10.1038/s41467-024-54151-y
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