Mechanisms of circadian clock interactions with aryl hydrocarbon receptor signalling

Per-Arnt-Sim (PAS) domain-containing proteins are critical to homeostatic regulatory networks that mediate responsiveness to environmental change. PAS domains are multifunctional structural motifs that allow protein-protein interactions amongst family members, typically forming heterodimeric transcription factors to affect the transcription of target genes. Prototypical PAS domain-dependent pathways include the circadian clock network and metabolic regulation of the xenobiotic response through the aryl hydrocarbon receptor (AhR). Both pathways are increasingly linked to health, and alteration in their function contributes to development of disease. The AhR demonstrates promiscuity in ligand binding and selectivity during heterodimer formation, which allows varied combinations of protein-protein interactions with other Per-Arnt-Sim (PAS) domain-containing proteins and crosstalk amongst signalling pathways, including the molecular clockworks. AhR and the circadian signalling pathways are highly integrated and reciprocally regulated. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR influences amplitude and phase of rhythms in circadian clock genes, hormones, and behaviour. Understanding the molecular interactions between AhR and the clock provides insight into physiological regulation of rhythmic processes and provides an innovative approach to development of therapeutics.