Aryl hydrocarbon receptor as a DNA methylation reader in the stress response pathway

The aryl hydrocarbon receptor (AhR) mediates various cellular responses upon exposure to exogenous and endogenous stress factors. In these responses, AhR plays a dual role as a stress sensor for detecting various AhR ligands and as a transcription factor that upregulates the expression of downstream effector genes, such as those encoding drug-metabolizing enzymes. As a transcription factor, it selectively binds to the unmethylated form of a specific sequence called the xenobiotic responsive element (XRE). We suggest that AhR is a novel DNA methylation reader, unlike classical methylation readers, such as methyl-CpG-binding protein 2, which binds to methylated sequences. Under physiological conditions of continuous exposure to endogenous AhR ligands, such as kynurenine, methylation states of the individual target XREs must be strictly regulated to select and coordinate the expression of downstream genes responsible for maintaining homeostasis in the body. In contrast, long-term exposure to AhR ligands frequently leads to changes in the methylation patterns around the XRE sequence. These data indicate that AhR may contribute to the adaptive cellular response to various stresses by modulating DNA methylation. Thus, the DNA methylation profile of AhR target genes should be dynamically controlled through a balance between robustness and flexibility under both physiological and stress conditions. AhR is a pivotal player in the regulation of stress response as it shows versatility by functioning as a stress sensor, methylation reader, and putative methylation modulator.

Automated summary

AhR functions as a stress sensor and a transcription factor, mediating cellular responses to various stress factors. It can selectively bind to a specific sequence called XRE, acting as a novel DNA methylation reader. AhR's role in regulating DNA methylation and contributing to adaptive cellular response to stress has been discovered.