Abstract
Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components, and act through β-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells leads to an enrichment of active Hnf4α enhancers according to a HOMER analysis. To model the functional significance of this predicted unusual enhancer utilization we generated single and compound knockouts of FoxO1 and Hnf4α in β-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 β-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 Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell “disallowed” genes; and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.