As with a symphony orchestra, the circadian orchestra is hierarchically organized, with the suprachiasmatic nucleus (SCN) of hypothalamus as its conductor. Circadian rhythm is generated by a transcriptional–translational feedback loop between two groups of clock genes: positive and negative elements. The circadian locomotor output cycles kaput (CLOCK) and the brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1), acting as positive elements, are responsible of the synthesis of two transcriptional factors, which after heterodimerization induce the expression of negative components of the molecular circadian clock such as periods (Pers 1, 2 and 3), cryptochromes (Cry1 and Cry2) and nuclear receptor subfamily 1 (REV-ERB-?). These negative elements, after dimerization (PER–CRY) undergo a nuclear translocation and act as suppressors of CLOCK and BMAL1 expression. Thus, the levels of positive and negative elements oscillate in antiphase with a period of approximately 24 h in SCN in vitro.
Some components of the molecular clock, such as REV-ERB-?, BMAL1 and CLOCK also induce a number of extra-clock genes, termed clock-controlled genes (CCG), which are not directly involved in the clock machinery but are able to induce the expression of many target genes.