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.

Keywords: Jun dimerization protein; aryl hydrocarbon receptor; chromatin control; nuclear factor erythroid 2-related factor 2; reactive oxygen species; transcriptional regulation.

Figure 1

Time course of promoter activity of DRE-, ARE-, and AP-1 luciferase in wild-type MEFs in response to TCDD. Wild-type MEFs were incubated with 10 nM TCDD, a phase I enzyme ligand, and the luciferase activity was measured at each time point using DRE-luciferase (red line), ARE-luciferase (blue line), AP-1 luciferase (brown line), and AHR-luciferase (light green) as described elsewhere . The schematic model represents the time course of each cis-element mutated luciferase as described elsewhere .

Figure 2

Modes of AHR promoter activation in a spatiotemporal manner. Schematic representation of TCDD-induced AHR activation through the AHR-JDP2, NRF2-JDP2, and AHR-NRF2 complexes to increase ROS production, cell spreading, and apoptosis in wild-type MEFs. In Jdp2^-/- MEFs, only a residual amount of AHR-ARNT is recruited to the DRE2 and DRE3 elements of the AHR promoter. Recruitment to DRE occurs at DRE2 and DRE3 after a 2-h exposure to TCDD. After 6-h exposure, this complex moves to ARE1 and ARE2 because AHR degradation starts via ubiquitin complex activity. After 24 h, the AHR activity is due to JDP2 binding to the AP-1 site in the AHR promoter. This TCDD-induced AHR promoter activation appears to be performed by the AHR-NRF2-JDP2 battery, as previously described .

Figure 3

Hypothetical modeling of the AHR-NRF2-JDP2 axis. Chromatin remodeling and epigenetic regulation of the AHR locus were involved in the function of histone acetylation and deacetylation of the AHR-NRF2 complex and the histone chaperone JDP2. In TCDD-induced MEFs, TCDD-bound AHR enters the nucleus and binds to ARNT within 2 h of exposure to TCDD. Then, AHR-ARNT recruits NRF2/sMAF and JDP2, which interact with SWI/SNF complexes, such as BRG1 and cohesin SM3, which in turn open the closed chromatin. Subsequently, AHR-ARNT with coactivator CBP/p300 binds to DRE2/3 of the AHR promoter. Then, RNA polymerase complexes are recruited to the transcription start site. After 6-h exposure to TCDD, the AHR-ARNT complex moves to the ARE1 site through the NRF2-sMAF complex, and recruits coactivator complexes, such as p160/SRE1/2/NCOA, pCIP/AIB/ACTR, and CBP/p300, with Pol II, mediator complex including MED16 , and cyclin-dependent kinase 9/cyclin T1, to mediate mRNA elongation with C-terminal domain phosphorylation in cooperation with positive transcription elongation factor b . After 24-h exposure, nuclear AHR is degraded, and the AP-1 site remains active for AHR transcription to maintain the coactivator complex. After greater than 24-h exposure to TCDD, JDP2 at the AP-1 site can recruit corepressors, such as nuclear receptor corepressor/silencing mediator for retinoic acid and thyroid hormone receptors and HDACs 1-6 and 10 and inhibit the histone demethylase activity mediated by lysine demethylase 6A and the coactivator CBP/p300 to terminate AHR RNA transcription and close the chromatin at the AHR locus. This Figure was published in Biochemical Pharmacology, Vol. 233, Wuputra K, Hsu WH, Ku CC, Yang YH, Kuo KK, Yu FJ, Yu HS, Nagata K, Wu DC, Kuo CH, Yokoyama KK, The AHR-NRF2-JDP2 gene battery: Ligand-induced AHR transcriptional activation., 116761, Copyright Elsevier B.V., 2025, and we were permitted to reuse and modify from Elsevier B.V.