| First Author | Bernardo E | Year | 2025 |
| Journal | Cell Metab | Volume | 37 |
| Issue | 9 | Pages | 1870-1889.e10 |
| PubMed ID | 40774250 | Mgi Jnum | J:371839 |
| Mgi Id | MGI:8241416 | Doi | 10.1016/j.cmet.2025.07.007 |
| Citation | Bernardo E, et al. (2025) HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes. Cell Metab |
| abstractText | Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic beta 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 beta cell-autonomous defects and identify direct beta 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 beta cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in beta 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 beta cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis. |
