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

Bernardo, E.; Vas, M.G.; Balboa, D.; Cuenca-Ardura, M.; Bonàs-Guarch, S.; Planas-Fèlix, M.; Mollandin, F.; Torrens-Dinarès, M.; Maestro, M.A.; Garcia-Hurtado, J.; Moratinos, S.; Ravassard, P.; Dou, H.Q.; Heyn, H.; Oudenaarden, A. van; Groen, N.; Koning, E. de; Conrad, C.; Eils, R.; Vernia, S.; Rorsman, P.; Ferrer, J.

doi:doi:10.1016/j.cmet.2025.07.007

Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic D 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 D cell-autonomous defects and identify direct D 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 D cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in D cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D...Show moreType 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic D 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 D cell-autonomous defects and identify direct D 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 D cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in D 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 D cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.Show less

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