| Popis: |
SummaryType II nuclear hormone receptors, such as FXR, LXR, and PPAR, which function in glucose and lipid metabolism and serve as drug targets for metabolic diseases, are permanently positioned in the nucleus regardless of the ligand status. Ligand activation of these receptors is thought to occur by co-repressor/co-activator exchange, followed by initiation of transcription. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent receptor binding. We show that chromatin accessibility, LXRα occupancy, and LXRα-dependent gene expression upon ligand activation require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when LXRα is bound by an agonist. Our results suggest that Foxa2 and LXRα bind DNA as an interdependent complex during ligand activation. Our model requiring pioneering activity for ligand activation challenges the existing co-factor exchange mechanism and expands current understanding of nuclear receptor biology, suggesting that chromatin accessibility needs to be considered in design of drugs targeting nuclear receptors. |
