Fig. 1

The mammalian circadian clock. a Schematic representation of the molecular clock. The transcriptional activators CLOCK:BMAL1 rhythmically bind to E-boxes (yellow rectangles) and activate expression of clock-controlled genes (CCG). Amongst these CCG, the circadian repressors Cry1-2 and Per1-3 are transcribed. Upon translation, Period complexes are ensembled in the cytoplasm, and distinct posttranslational modifications control its activity (red stars). Nuclear translocated Period complexes sequester CLOCK:BMAL1 transactivator heterodimers, hereby interrupting transcription of CCG. Proteasomal degradation fine tunes clearance of repressors from the nucleus. Reinforcing loops include the interplay between REV-ERB and ROR proteins at ROR elements (blue rectangles) in the promoters of many genes, including that of Bmal1. Additionally, certain transcription factors are clock controlled, as exemplified by the PAR-bZip family including the activators DBP, TEF, and HLF and the repressor NFIL3. Through binding to D-boxes in the genome (red rectangles), these can impose rhythmicity to specific genetic programs, such as demonstrated for components of the cytochrome P450 system in the mouse liver [106]. b Distinct epigenetic regulatory layers coordinate circadian transcriptional output. Tissue-specific transcription factors, nuclear receptors, or master regulators of intracellular signaling can determine a portion of the circadian transcriptome in response to environmental cues. Additionally, epigenetic modifications including DNA methylation or histone marks are highly dynamic and shape circadian transcription. Indeed, the global nuclear architecture has been demonstrated to coordinate transitions between transcriptionally active and repressive states during the circadian cycle