XREs

Xenobiotic response elements, or XREs, are cis-regulatory DNA sequences that mediate transcriptional responses to xenobiotic compounds via the aryl hydrocarbon receptor (AHR) pathway. They are located in the promoter or enhancer regions of target genes and function as binding sites for the AHR-ARNT transcriptional complex.

When a ligand such as a dioxin or other aromatic hydrocarbon binds AHR, the receptor translocates to the nucleus, dimerizes with ARNT, and binds XRE motifs. These motifs often contain a core sequence around GCGTG, though there is variability. Binding recruits coactivators and the transcriptional machinery, increasing expression of detoxification genes such as CYP1A1, CYP1A2, CYP1B1, and other phase I and II enzymes like NQO1 and GSTs. The arrangement of XREs—how many there are, their orientation, and their spacing—along with interactions with other transcription factors, shapes the strength and tissue specificity of the response.

XRE activity is dose- and time-dependent and can vary across species and tissues due to differences in XRE sequences and AHR signaling components. Environmental pollutants that activate AHR, including dioxins and polycyclic aromatic hydrocarbons, can induce these genes and influence drug metabolism and toxic responses, with implications for cancer risk, development, and immune function.

Research on XREs employs reporter assays, chromatin immunoprecipitation, and genome-wide mapping to identify binding sites and target genes, contributing to understanding xenobiotic metabolism and AHR biology. See also aryl hydrocarbon receptor, ARNT, and CYP1A1.