Disruption of CLOCK-BMAL1 Transcriptional Activity Is Responsible for Aryl Hydrocarbon Receptor–Mediated Regulation of Period1 Gene

• Published in: Toxicological sciences 2010-05, Vol.115 (1), p.98-108
• Main Authors: Xu, Can-Xin, Krager, Stacey L., Liao, Duan-Fang, Tischkau, Shelley A.
• Format: Article
• Language: English
• Subjects: AhR activation; Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; BMAL1; Carcinoma, Hepatocellular; Cell Line, Tumor; circadian rhythm; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Down-Regulation; Ebox; Environmental Pollutants - toxicity; Gene Expression Regulation - drug effects; gene regulation; Hepatocytes - drug effects; Hepatocytes - physiology; liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Molecular Toxicology; Per1; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Polychlorinated Dibenzodioxins - toxicity; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; RNA, Messenger - metabolism; Transcription, Genetic - drug effects
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfq022

The aryl hydrocarbon receptor (AhR) is a period-aryl hydrocarbon receptor nuclear transporter-simple minded domain transcription factor that shares structural similarity with circadian clock genes and readily interacts with components of the molecular clock. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters behavioral circadian rhythms and represses the Period1 (Per1) gene in murine hematopoietic stem and progenitor cells. Per1 expression is driven by circadian locomotor activity cycles kaput-brain muscle ARNT-like (CLOCK-BMAL1)–dependent activation of Eboxes in the Per1 promoter. We hypothesized that the effects of AhR activation on the circadian clock are mediated by disruption of CLOCK-BMAL1 function and subsequent Per1 gene suppression. Effects of AhR activation on rhythmic Per1 transcripts were examined in livers of mice after treatment with the AhR agonist, TCDD; the molecular mechanisms of Per1 repression by AhR were determined in hepatoma cells using TCDD and β-napthoflavone as AhR activators. This study reports, for the first time, that AhR activation by TCDD alters the Per1 rhythm in the mouse liver and that Per1 gene suppression depends upon the presence of AhR. Furthermore, AhR interaction with BMAL1 attenuates CLOCK-BMAL1 activity and decreases CLOCK binding at Ebox1 and Ebox3 in the Per1 promoter. Taken together, these data suggest that AhR activation represses Per1 through disrupting CLOCK-BMAL1 activity, producing dysregulation of rhythmic Per1 gene expression. These data define alteration of the Per1 rhythm as novel signaling events downstream of AhR activation. Downregulation of Per1 could contribute to metabolic disease, cancer, and other detrimental effects resulting from exposure to certain environmental pollutants.