Figure 1.

At a molecular level, the mammalian circadian clock is composed of a group of clock genes that regulate their own transcription and translation in a series of interlocking negative feedback loops. Heterodimers of the transcription factors BMAL1 and CLOCK drive the expression of the Period (Per1/Per2) and Cryptochrome (Cry1/Cry2) genes, the nuclear receptors retinoid-related orphan receptor (RORα) and REV-ERBα, and a number of downstream genes referred to as clock-controlled genes (CCGs). The protein products of the Per and Cry genes dimerize and inhibit the transcriptional activity of CLOCK-BMAL1. A number of kinases, such as casein kinase 1ɛ/δ (CK1 ɛ/δ), regulate the activity of PER-CRY dimers at a post-transcriptional level. RORα and REV-ERBα also regulate the transcription of BMAL1, whereby RORα promotes its expression, whereas REV-ERBα inhibits it. This cycle of clock gene expression completes in approximately 24 h (Huang et al., 2011; Mohawk et al., 2012).