The AHR–NRF2–JDP2 gene battery: Ligand–induced AHR transcriptional activation

Abstract

Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the “AHR–NRF2 gene battery”. The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in the transcription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR–AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR–NRF2 gene battery as the AHR–NRF2–JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR–NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR–NRF2–JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.