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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 \u03b2 cells during pancreatic differentiation. Mechanistically, this risk-G variant greatly enhances RXRA binding and over-activates <jats:italic>FOXA2<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41467-024-54151-y","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T06:36:38Z","timestamp":1731393398000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA"],"prefix":"10.1038","volume":"15","author":[{"given":"Yinglei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiafei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6463-7356","authenticated-orcid":false,"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"54151_CR1","doi-asserted-by":"publisher","first-page":"e142244","DOI":"10.1172\/JCI142244","volume":"131","author":"H Zhang","year":"2021","unstructured":"Zhang, H., Colclough, K., Gloyn, A. 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