Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function.

ABSTRACT:

Objective

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.

Methods

In this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α 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 Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea a

SUBMITTER: Kuo T 

PROVIDER: S-EPMC8225970 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature