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bioRxiv · 10.1101/2020.07.04.187864

Antagonistic epistasis of Hnf4a and FoxO1 networks through enhancer interactionsin beta-cell function

Kuo, T.·Du, W.·Miyachi, Y.·Dadi, P. K.·Jacobson, D. A.·Accili, D.
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Abstract

Genetic and acquired abnormalities contribute to pancreatic {beta}-cell failure in diabetes. Transcription factors Hnf4 (MODY1) and FoxO1 are respective examples of these two components, and are known to act through {beta}-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature {beta}-cells leads to increased selection of FoxO1 enhancers by Hnf4. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4 in {beta}-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. 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. Gene expression analyses revealed the reversal of {beta}-cell dysfunction with an antagonistic network regulating glycolysis, including {beta}-cell "disallowed" genes; and that 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 {beta}-cell dysfunction.

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Kuo, T., Du, W., Miyachi, Y., Dadi, P. K., Jacobson, D. A., Accili, D.. 2020-07-05. Antagonistic epistasis of Hnf4a and FoxO1 networks through enhancer interactionsin beta-cell function. https://doi.org/10.1101/2020.07.04.187864

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