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

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...

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Main Authors: Bernardo, Edgar (Author) , De Vas, Matías Gonzalo (Author) , Balboa, Diego (Author) , Cuenca-Ardura, Mirabai (Author) , Bonàs-Guarch, Sílvia (Author) , Planas-Fèlix, Mercè (Author) , Mollandin, Fanny (Author) , Torrens-Dinarès, Miquel (Author) , Maestro, Miguel Angel (Author) , García-Hurtado, Javier (Author) , Moratinos, Sonia (Author) , Ravassard, Philippe (Author) , Dou, Haiqiang (Author) , Heyn, Holger (Author) , van Oudenaarden, Alexander (Author) , Groen, Nathalie (Author) , de Koning, Eelco (Author) , Conrad, Christian (Author) , Eils, Roland (Author) , Vernia, Santiago (Author) , Rorsman, Patrik (Author) , Ferrer, Jorge (Author)
Format: Article (Journal)
Language:English
Published: August 6 2025
In: Cell metabolism
Year: 2025, Volume: 37, Issue: 9, Pages: 1870-1889.e1-e10
ISSN:1932-7420
DOI:10.1016/j.cmet.2025.07.007
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.cmet.2025.07.007
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1550413125003341
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Author Notes: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, and Jorge Ferrer
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Summary: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.
Item Description:Gesehen am 23.02.2026
Physical Description:Online Resource
ISSN:1932-7420
DOI:10.1016/j.cmet.2025.07.007

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