Genome-wide analysis reveals ligand-dependent allostery in RARα:RXR-mediated transcriptional regulation

Transcriptional regulation by nuclear hormone receptors is controlled by allosteric mechanisms linking ligand binding to DNA recognition and gene expression. We investigated the genomic consequences of ligand-induced allostery in the retinoic acid receptor-α (RARα):retinoid X receptor (RXR) heterodimer using untransfected pancreatic acinar cells. CUT&RUN and RNA sequencing show that distinct combinations of receptor-specific agonists-RARα(AM580) and RXR(CD3254)-drive unique DNA-binding profiles (RAR response elements [RAREs]) and transcriptomes. Doubly liganded heterodimers recognize specific RAREs and activate gene networks distinct from singly liganded states or the pan-agonist 9-cis retinoic acid. RXR ligands exert potent allosteric effects, modulating DNA binding and gene expression, and, with RARα ligands, fine-tune transcriptional outcomes. Motif and Gene Ontology analyses confirm ligand-identity-controlled genomic targeting. Unliganded heterodimers show no unique binding, suggesting non-productive or indirect DNA interactions. These results link receptor-ligand allostery to large-scale transcriptional reprogramming, highlighting genome-wide mechanisms whereby subtle structural changes propagate to functional specificity, with implications for physiology and therapeutic targeting in cancer and metabolic disorders.