New insights into coordinated regulation of AHR promoter transcription; molecular mechanisms and therapeutic targets.

Abstract

The aryl hydrocarbon receptor (AHR) plays crucial roles in the control of stress, xenobiotic metabolism, inflammation, and cancer. However, information on the chromatin regulation of ligand-dependent AHR promoter activation is limited. AHR and nuclear factor erythroid 2-related factor 2 (NRF2) signaling are coordinated to maintain the balance of reactive oxygen species (ROS), which is termed the AHR-NRF2 gene battery. Recently, promoter activation of AHR to phase I ligands was reported to be regulated by AHR-NRF2-Jun dimerization protein 2 (JDP2) in a spatiotemporal manner. Tight coupling between phase I and II nuclear transcriptional factor complexes through histone chaperone JDP2 in a time- and space-dependent manner may occur in the chromatin to regulate phase I gene expression. This new mechanism, termed AHR-NRF2-JDP2 gene battery, may facilitate the identification of therapeutics at the reduction of reactive toxic intermediates at the nucleosome level. Identifying the AHR-NRF2-JDP2 gene battery mechanisms will enable the development of novel therapeutics for the risk assessment of oxidative stress/antioxidation, detoxification, ROS, cell death, inflammation, allergies, and cancer.