OR33-06 Pioneer Factor Foxa2 Mediates Chromatin Conformation Changes In Ligand-dependent Activation Of FXR

Abstract

Abstract Disclosure: Y. Hao: None. L. Han: None. C. Wu: None. I. Bochkis: None. Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in pharmacology to develop drug targets for diverse medical conditions, including metabolic disease and cancer. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation (Kain et al., Molecular Metabolism, 2021). FXR is activated by bile acids and we have demonstrated that Foxa2 plays an important role in bile acid metabolism, as deletion of Foxa2 in the liver results in intrahepatic cholestasis (Bochkis et al., Nature Medicine, 2008). We hypothesized that in addition to increasing chromatin accessibility, Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP (chromatin conformation capture, Hi-C, combined with chromatin immunoprecipitation, ChIP) assay to assess Foxa2-dependent long-range interactions in mouse livers treated with vehicle and FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. In addition, ligand-treated livers have more Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes in ligand-dependent FXR activation. We show that chromatin conformation, including genome-wide interactions, intra-chromosomal and inter-chromosomal loops, drastically changes upon addition of FXR agonist. Hence, Foxa2 enables these conformational changes and plays an extended role in bile acid metabolism. Presentation: Sunday, June 18, 2023