In the positive feedback loop the transcription factors Bmal1 and Clock activate the transcription of Period (Per) and Cryptochrome (Cry) genes, as well as that of clock-controlled genes (CCGs). In the cytoplasm, PERIOD and CRYPTOCHROME proteins heterodimerize, enter the nucleus and interact with BMAL1/CLOCK, inhibiting the transactivation of their own promoters (negative feedback). BMAL1 and CLOCK also stimulate the transcription of Rev-Erba and Rora (Adapted from Tosini et al., BioEssays, 2008).