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

Yinglei Li, Ran Zheng, Lai Jiang, Chenchao Yan, Ran Liu, Luyi Chen, Wenwen Jin, Yuanyuan Luo, Xiafei Zhang, Jun Tang, Zhe Dai and Wei Jiang ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54151-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54151-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54151-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().