Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα

• DOI: 10.1016/j.molmet.2021.101291
• Publication Date: 2021-07-08T18:09:47Z
• Authors: Jessica Kain; Xiaolong Wei; Nihal A. Reddy; Andrew J. Price; Claire Woods; Irina M. Bochkis
• Keywords: Farnesoid X receptor; Liver X receptor; FOXA2

Type II nuclear hormone receptors, including farnesoid X receptors (FXR), liver (LXR), and peroxisome proliferator-activated (PPAR), which serve as drug targets for metabolic diseases, are permanently positioned in the nucleus thought to be bound DNA regardless of ligand status. However, recent genome-wide location analysis showed that LXRα PPARα binding is largely ligand-dependent. We hypothesized pioneer factor Foxa2 evicts nucleosomes enable ligand-dependent type performed studies test this hypothesis. ATAC-Seq was used profile chromatin accessibility; ChIP-Seq assess transcription factors (Foxa2, FXR, LXRα, PPARα) binding; RNA-Seq determined differentially expressed genes wildtype mutants treated with a (GW4064 GW3965, T09 LXRα). reveal accessibility, FXR binding, occupancy, ligand-responsive activation gene expression by require Foxa2. Unexpectedly, occupancy drastically increased when either receptor, or an agonist. In addition, co-immunoprecipitation experiments demonstrate interacts receptor manner, suggesting bind interdependent complex during activation. Furthermore, induced LXR ligands, leading targets. Our model requires pioneering activity challenges existing ligand-independent mechanism. also required achieve proper – one binds added repressing competing receptor.