The core circadian clock mechanism is composed of 2 interlocked transcriptional negative feedback loops14. In the primary loop, transcriptional activators, BMAL1 (ARNTL) and CLOCK (or its ortholog NPAS2), form a DNA-binding heterodimer and drive expression of the PER1-3 and CRY1/2 genes, which ultimately repress BMAL1-CLOCK activity in a feedback manner. This loop also drives rhythmic expression of the nuclear hormone receptors, NR1D1 (Rev-erbα) and NR1D2 (Rev-erbβ), which in turn rhythmically repress the expression of BMAL1 and CLOCK as the second loop15.
