FIGURE 1.

Components of the circadian molecular system. The circadian molecular system is made up of a transcriptional feedback loop defined by the interlocking positive and negative limbs. The positive limb is comprised of two core genes: Clock and Bmal1. CLOCK and BMAL1 form a heterodimer and bind to E-box sequences activating the three negative limbs of the system. The first negative limb is the Per and Cry genes. Upon translation, the PER and CRY proteins form a heterodimer and repress the transcription of the Clock and Bmal1 complex. The second negative limb is the Rev-erb and Ror genes. The proteins REV-ERB and ROR compete for the RORE sequence binding site, which is present in many genes. Upon binding, ROR induces the gene’s transcription, whereas REV-ERB inhibits the gene’s transcription. Those genes include Bmal1, a core component of the positive limb, thus creating this second negative feedback loop, and Nfil3, which will contribute in the feedback loop of the third negative limb. The third negative limb is made up of the PAR bZIP transcription factors, namely the genes Dbp, Hlf, and Tef. These PAR bZIP transcription factors compete with Nfil3 for D-box sequence binding. The PAR bZIP proteins bind to the D-box sequence to activate transcription, whereas NFIL3 represses transcription. The D-box sequence is present within the promoter sequence of Rev-erb and Ror genes. Thus, the PAR bZIP genes and Nfil3 create a third negative feedback loop and indirectly affect Bmal1 transcription through its regulation of Rev-erb and Ror transcription. Together, the positive limb and these three negative limbs form the circadian molecular system whose functional output is the circadian rhythm