| First Author | Kuo T | Year | 2021 |
| Journal | Mol Metab | Volume | 53 |
| Pages | 101256 | PubMed ID | 34048961 |
| Mgi Jnum | J:318686 | Mgi Id | MGI:6814872 |
| Doi | 10.1016/j.molmet.2021.101256 | Citation | Kuo T, et al. (2021) Antagonistic epistasis of Hnf4alpha and FoxO1 metabolic networks through enhancer interactions in beta-cell function. Mol Metab 53:101256 |
| abstractText | OBJECTIVE: Genetic and acquired abnormalities contribute to pancreatic beta-cell failure in diabetes. Transcription factors Hnf4alpha (MODY1) and FoxO1 are respective examples of these two components and act through beta-cell-specific enhancers. However, their relationship is unclear. METHODS: In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature beta-cells enriches active Hnf4alpha enhancers according to a HOMER analysis. RESULTS: To model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4alpha in beta-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective beta-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4alpha. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of beta-cell dysfunction. An antagonistic network regulating glycolysis, including beta-cell "disallowed" genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. CONCLUSIONS: The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of beta-cell dysfunction. |
