FIGURE 1.

Circadian clock transcription‐translation feedback loops. In primary TTFL, phosphorylated BMAL1:CLOCK/NPAS2 is translocated into the nucleus and initiates the transcription of related genes by binding to the promoter regions E‐box (5′‐CACGTG‐3′) of several genes, including the core clock genes Cryptochrome (CRYs), Period (PERs), REV‐ERBs and retinoic acid receptor‐related orphan receptors (RORs). The PER and CRY proteins accumulate in the cytoplasm, enter the nucleus and inhibit the transcription and phosphorylation of BMAL1 and CLOCK. Consequently, further production of clock proteins in inhibited. In another feedback pathway, RORs and REV‐ERBs proteins competitively bind to ROR elements (ROREs) near the BMAL1 promoter. While REV‐ERBs inhibit the transcription of BMAL1, RORs promote the process. As such, REV‐ERBs show a strong circadian rhythm that is aligned with the rhythm of BMAL1. Additionally, D‐box binding protein (DBP), regulated by E‐box and the mammalian transcription factor E4 binding protein 4 (E4BP4; regulated by ROREs), accommodate the expression of PER gene through D‐box and, in turn, affect E‐box activity.⁶ Overall, these three cis‐acting elements coordinate a circadian cycle over approximately 24 h