The farnesoid X-receptor (FXR), a nuclear receptor, is a ligand-regulated transcription factor that regulates bile acid, lipid, and glucose metabolism. FXR consists of a ligand-binding domain (LBD) that binds small lipophilic ligands and a DNA binding domain (DBD) that targets specific areas of DNA called FXR response elements (FXRE). When ligands bind to the LBD, allosteric structural changes occur in the DBD, affecting the DNA binding preferences. Once bound to FXREs, ligand-bound FXR regulates the transcription of specific genes. While the natural ligands of FXR are bile acids, many synthetic ligands have also been developed to regulate FXR. Previous studies have shown that structurally similar FXR ligands activate FXR in a gene-specific fashion. However, it is unclear how these similar FXR ligands achieve such varying effects on DNA binding preferences. My project focuses on endogenous and synthetic FXR ligands and aims to understand how ligand structure impacts FXR-DNA binding. To investigate how modifications in the ligand scaffold regulate FXR transcriptional activity, I am performing dual-luciferase assays to measure the transcription levels in a large set of FXRE-driven promoters and assess the impact of FXR mutations on transcription.
