Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Nat Commun. 2024 Nov 12;15(1):9771. doi: 10.1038/s41467-024-54151-y.
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.
人类遗传学分析已经确定了许多与糖尿病特征相关的非编码单核苷酸多态性，但这些变体是否以及如何导致糖尿病在很大程度上是未知的。在这里，我们关注一个非编码变体 rs6048205，并报告说风险-G 变体损害了 PDX1+/NKX6-1+胰腺祖细胞的产生，并且进一步导致在胰腺分化过程中功能性 β 细胞的异常减少。在机制上，这种风险-G 变体极大地增强了 RXRA 的结合并过度激活了 FOXA2 的转录，特别是在胰腺祖细胞阶段，这反过来又抑制了 NKX6-1 的表达。一致地，诱导性 FOXA2 过表达可以模拟分化缺陷。更重要的是，携带风险-G 的小鼠表现出异常的胰岛结构，并且对链脲佐菌素或高脂肪饮食更敏感，最终发展为糖尿病。这项研究不仅确定了糖尿病易感性中的一个因果非编码变体，而且还通过招募特定于阶段的因子来剖析潜在的功能获得机制。
