Figure 1.

Role of BMAL1 in the circadian rhythm. The circadian rhythm involves a negative-feedback loop and an accessory feedback loop. In the negative-feedback loop, the CLOCK and BMAL1 form a heterodimer that activates the PER and CRY genes by directly interacting with the E-Box element. Subsequently, accumulation of PER/CRY protein complexes inhibits the expression of BMAL1/CLOCK. In the accessory feedback loop, the transcription of BMAL1/CLOCK is controlled by positive regulators (RORα, RORβ and RORγ) and negative regulators (REV-ERBα and REV-ERBβ). ClOCK and BMAl1, in turn, regulate the expression of RORs and REV-ERBs.