HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic b-cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor Hepatocyte Nuclear Factor-1alpha, is the most commonly mutated gene in Mendelian diabetes, yet also carries loss- or gain-of-function coding variants that predispose or protect against polygenic T2D, respectively. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β-cell-autonomous defects, and identify direct b-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 b-cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β-cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF associate 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.
Date Issued
2025-09-02
Date Acceptance
2025-07-09
Citation
Cell Metabolism, 2025, 37 (9), pp.1870-1889.e10
ISSN
1550-4131
Publisher
Cell Press
Start Page
1870
End Page
1889.e10
Journal / Book Title
Cell Metabolism
Volume
37
Issue
9
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Publication Status
Published
Date Publish Online
2025-08-06