Two major interconnected molecular loops in the circadian machinery. The circadian machinery includes two interconnected molecular loops. In both of these loops, circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) are the key players, and they form a dimer complex. In the core loop, the CLOCK:BMAL1 complex binds to enhancer-boxes (E-boxes) of some of its target genes, including cryptochrome circadian clock 1 (CRY1), CRY2, period circadian clock 1 (PER1), and PER2, and activates their expression. When the amount of CRY and PER proteins reaches a critical level, they suppress the activity of the CLOCK:BMAL1 complex. In this way, they suppress their own expression by forming a negative feedback loop. In the secondary loop, the CLOCK:BMAL1 complex binds to E-boxes in two genes, nuclear receptor subfamily 1 group D member 1 (NR1D1) and RAR-related orphan receptor A (RORA), and activates their expression. The genes NR1D1 and RORA code for two nuclear receptors, nuclear receptor subfamily 1 group D member 1 (REV-ERBα) and RORα, respectively. These two nuclear receptors compete with each other to bind to a shared DNA-binding element called RORE within the BMAL1 promoter. RORα activates the transcription of BMAL1, while REV-ERBα represses BMAL1 expression. These two molecular loops impact each other by affecting the activity and expression of BMAL1 in a circadian fashion.