巴塞罗那科技学院Jorge Ferrer小组宣布他们的最新研究揭示了HNF1A和A1CF协调β细胞转录剪接轴，该轴在2型糖尿病中被破坏。相关论文于2025年8月6日发表在《细胞—代谢》杂志上。

该研究组现在证明糖尿病是由β细胞自主细胞缺陷引起的，并确定了HNF1A的直接β细胞基因组靶点。这揭示了一个调控轴，HNF1A控制A1CF的转录，A1CF协调RNA剪接程序，包括调节β细胞功能的基因。这种HNF1A-A1CF转录剪接轴在T2D个体的β细胞中被抑制，而减少胰岛A1CF的遗传变异与血糖升高和T2D易感性相关。因此，他们的发现确定了一个线性层次结构，该结构协调β细胞特异性转录和剪接程序，并将该途径与T2D发病机制联系起来。

据介绍，2型糖尿病（T2D）是一种以胰腺β细胞功能障碍和胰岛素抵抗为特征的破坏性慢性疾病，其病理生理机制尚不清楚。HNF1A编码转录因子肝细胞核因子-1 α，是孟德尔型糖尿病中最常见的突变基因。HNF1A也携带功能缺失或功能获得的编码变体，分别易患或预防多基因T2D。然而，HNF1A缺陷型糖尿病的发病机制尚不清楚。

附：英文原文

Title: HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes

Author: Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Patrik Rorsman, Jorge Ferrer

Issue&Volume: 2025-08-06

Abstract: Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. HNF1A also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of A1CF, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.

DOI: 10.1016/j.cmet.2025.07.007

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00334-1