All cells have an approximate 24-hour negative feedback loop of core circadian proteins, PER1/2, CRY1/2, BMAL1, and CLOCK. PERs and CRYs, expressed upon BMAL1 and CLOCK binding to the E-box in their promoter regions, accumulate in the cytoplasm during the day. PERs and CRYs form a heterodimer and translocate back to the nucleus where they inhibit their transcriptional activators, BMAL1 and CLOCK, thereby inhibiting their own expression. Nuclear receptors like RORs and REV-ERBs regulate BMAL1 expression by either acting as activators or repressors, respectively.