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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
August 6 2025
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| In: |
Cell metabolism
Year: 2025, Jahrgang: 37, Heft: 9, Pages: 1870-1889.e1-e10 |
| ISSN: | 1932-7420 |
| DOI: | 10.1016/j.cmet.2025.07.007 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes |c 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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| 520 | |a 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. | ||
| 650 | 4 | |a gene regulatory networks | |
| 650 | 4 | |a gene transcription | |
| 650 | 4 | |a genetics of diabetes | |
| 650 | 4 | |a HNF1 homeobox A | |
| 650 | 4 | |a HNF1A | |
| 650 | 4 | |a human embryonic stem cell-derived islets | |
| 650 | 4 | |a human genetics | |
| 650 | 4 | |a MODY-3 | |
| 650 | 4 | |a pancreatic beta cells | |
| 650 | 4 | |a pancreatic islets | |
| 650 | 4 | |a RNA splicing | |
| 650 | 4 | |a splicing factor networks | |
| 650 | 4 | |a type 2 diabetes | |
| 700 | 1 | |a De Vas, Matías Gonzalo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Balboa, Diego |e VerfasserIn |4 aut | |
| 700 | 1 | |a Cuenca-Ardura, Mirabai |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Vernia, Santiago |e VerfasserIn |4 aut | |
| 700 | 1 | |a Rorsman, Patrik |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ferrer, Jorge |e VerfasserIn |4 aut | |
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