HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes
Year: 2025
Type: article
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.
Source: Cell Metabolism
Authors: 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
Institutions: Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, Imperial College London, Génétique Animale et Biologie Intégrative, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut des Sciences Moléculaires, Institut du Cerveau, University of Gothenburg, Centro Nacional de Análisis Genómico, University Medical Center Utrecht, Oncode Institute, Royal Netherlands Academy of Arts and Sciences, Leiden University Medical Center, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, University Hospital Heidelberg, MRC London Institute of Medical Sciences, Churchill Hospital, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: European Molecular Biology Organization, Vanderbilt University, National Institute on Handicapped Research, European Molecular Biology Laboratory, Boehringer Ingelheim Fonds, Generalitat de Catalunya, Vetenskapsrådet, Ministerio de Ciencia e Innovación, HORIZON EUROPE Framework Programme, Medical Research Council, European Research Council, H2020 European Research Council, H2020 Marie Skłodowska-Curie Actions, H2020 LEIT Space, Departament de Recerca i Universitats, Generalitat de Catalunya
Awards: G4497335113, Targeting etiologic molecular mechanisms to treat human diabetes, G5686866521, Expanding the genetic etiological and diagnostic spectrum of monogenic diabetes mellitus, G8371497876, G8682606578, Recruitment of Professor Patrik Rorsman and the establishment of a "metabolic physiology" unit at the University of Goteborg
OpenAlex ID: W4413020938