Fig. 2

Schema of the circadian clock system—the transcription-translation feedback loops. The circadian clock consists of a network of TTFL that generates endogenous circadian rhythm. TTFL includes two loops: (1) The first loop of TTFL begins with BMAL1:CLOCK complex translocating into the nucleus, activating transcription of target genes containing E-box cis-regulatory enhancer sequences in their promoter regions, such as PER and CRY. The CRY and PER are then transferred to the nucleus and interact with CLOCK:BMAL1 complex to inhibit their own transcription. The decrease of PER and CRY protein levels reduces the suppression of BMAL1:CLOCK activity, which allows for the establishment of a new oscillatory cycle. (2) In the second loop, the REV-ERBα/β repressor and the RORα/β activator proteins co-maintain the periodic expression of BMAL1