Figure 1

Molecular machinery of the circadian clock. The core clock components CLOCK and BMAL1 heterodimerize in the cytoplasm, forming a protein complex. The heterodimer is then translocated to the nucleus and binds to E-boxes on the promoter of target genes, controlling their expression. These genes include Per1, Per2, Per3, Cry1, Cry2, Reverbα, Rorα and many clock-controlled genes (CCGs). CLOCK/BMAL1 heterodimer also stimulates transcription of Bmal1 itself, forming the positive feedback loop of the mechanism. Negative feedback loop is mainly regulated by CRY and PER, that heterodimerize in the cytoplasm, translocate to the nucleus and inhibits CLOCK/BMAL1 transcription activity. Gene expression of Bmal1 is also regulated by REVERBα (inhibition) and RORα (stimulation), that compete for the same ROR elements present in the Bmal1 promoter. Regulation of CCGs expression by the circadian clock confers rhythmicity to a variety of molecular and physiological processes. Straight lines: stimulation. Dashed lines: inhibition.