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

Area of Science:

• Molecular Biology
• Genomics
• Endocrinology

Background:

• Nuclear hormone receptors regulate gene expression via allosteric mechanisms.
• Ligand binding influences DNA recognition and transcriptional activity.
• The retinoic acid receptor-alpha (RARα):retinoid X receptor (RXR) heterodimer is a key regulator.

Purpose of the Study:

• To investigate the genomic consequences of ligand-induced allostery in the RARα:RXR heterodimer.
• To understand how distinct ligand combinations affect DNA binding and gene expression.
• To explore therapeutic implications in cancer and metabolic disorders.

Main Methods:

• Utilized CUT&RUN and RNA sequencing in untransfected pancreatic acinar cells.
• Applied specific agonists RARα(AM580) and RXR(CD3254) to study heterodimer behavior.
• Performed Motif and Gene Ontology analyses for genomic targeting insights.

Main Results:

• Distinct ligand combinations (RARα, RXR, or both) induced unique DNA-binding profiles (RAR response elements [RAREs]) and transcriptomes.
• Doubly liganded heterodimers targeted specific RAREs, activating distinct gene networks.
• RXR ligands showed potent allosteric modulation of DNA binding and gene expression, fine-tuning outcomes with RARα ligands.

Conclusions:

• Receptor-ligand allostery drives large-scale transcriptional reprogramming.
• Ligand identity dictates genome-wide targeting and functional specificity.
• Findings have implications for understanding physiology and therapeutic strategies in diseases like cancer and metabolic disorders.