Fig. 2

The molecular clock. The molecular clock is composed of the main loop, the ROR/REV-ERB loop, and the PAR-bZIP loop. In the main loop, circadian clock genes BMAL1 and CLOCK heterodimerize and bind to E-box regions to induce transcription of other circadian clock genes such as CRY and PER which upon accumulation, heterodimerize to inhibit their own transcription. CRY and PER are later targeted for proteasomal degradation. In the PAR-bZIP loop, BMAL1 and CLOCK bind to E-box regions to modulate the transcription of PAR-bZIP factors DBP, TEF, and HLF. In the ROR/REV-ERB loop, BMAL1 and CLOCK bind to E-box regions to promote transcription of REV-ERBα/β, which bind to RORE to inhibit BMAL1 and NFIL3 transcription. In addition, PAR-bZIP factors bind to D-Box regions in the ROR/REV-ERB loop to promote transcription of ROR α/β, which then binds to RORE to stimulate transcription of BMAL1 and NFIL3