Trends in Cell Biology
ReviewMolecular architecture of the mammalian circadian clock
Section snippets
A clockwork physiology
Mammalian physiology and behavior are coordinated by an intrinsic molecular clock into rhythms that are synchronized with the 24 h solar day. Circadian (Latin circa diem, meaning ‘about a day’) synchronization allows anticipation of regular environmental changes to influence molecular and behavioral decisions that impact fitness and survival, including food intake and metabolism, predator/prey interactions, and the evasion of DNA damage from environmental insults, amongst others [1]. Circadian
A hierarchical timing system
Circadian rhythms are genetically encoded by a molecular clock located in nearly every cell that generates internal timing of approximately 24 h in the absence of external cues (Box 1). Molecular clocks located throughout the body in peripheral tissues are organized into a coherent, hierarchical system by a ‘master’ clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus [4]. The SCN is comprised of approximately 20 000 neurons that form a highly unified circadian network [5].
Peripheral clocks regulate tissue-specific expression patterns
Early microarray studies revealed that peripheral clocks regulate vast transcriptional programs to induce a single peak of expression once per day for each of the clock-controlled genes, representing approximately 10% of all expressed genes. These oscillating messenger RNA transcripts are specifically coordinated with tissue function, resulting in only ∼1–3% convergence in oscillating transcripts between liver, heart, muscle, and the SCN 28, 29, 30. Comparing clock-driven transcripts in the
Insight into the molecular clock mechanism
The heterodimeric CLOCK:BMAL1 complex is the essential positive regulator of circadian transcription in mammals, binding to several thousand sites throughout the genome in the liver with peak occupancy midday at circadian time (CT) CT5–8 (approximately 11 am to 2 pm) 39, 42. CLOCK:BMAL1 binding occurs primarily at consensus E-box DNA motifs and recruits complexes of the integral clock protein transcriptional repressors PER1, PER2, CRY1, and CRY2, with peak occupancy in the evening at CT15–18 [39]
Post-transcriptional/translational control of circadian output
Generation of the 24 h molecular clock that drives circadian changes in physiology and behavior is rooted in transcriptional regulation of integral clock genes, although it is surprisingly resilient to a reduction in overall transcriptional rates [92]. Outside these integral clock genes, post-transcriptional/translational regulation likely helps to provide additional flexibility by generating rhythms in mRNA transcripts or proteins in a tissue- or stimulus-dependent manner. For example, genes
Concluding remarks
Our lives are intimately tied to the external environment through the interaction of our intrinsic molecular clocks with the solar cycle. Knowledge of how internal clocks drive 24 h timing to temporally coordinate physiology has improved in recent years, but we still lack fundamental insight into the molecular basis of circadian timing and tissue-dependent control of physiology. Although built upon transcription-based feedback loops, it now appears that the majority of clock-controlled processes
Acknowledgments
We would like to thank the anonymous reviewers for their insightful comments and helpful suggestions. This work was supported by the National Institutes of Health (NIH P50 MH074924 and R01 MH078024 to J.S.T. and NIH P50 MH074924, R01 GM090247 and R21 NS079986 to C.B.G.) and by start-up funds from the University of California Santa Cruz (C.L.P.). J.S.T. is an Investigator in the Howard Hughes Medical Institute.
Glossary
- Circadian time (CT)
- a standard of time based on the internal free-running period of a circadian clock. By convention, the onset of activity in diurnal organisms defines circadian time zero (CT 0; usually 6 am), whereas the onset of activity in nocturnal organisms defines circadian time 12 (CT 12).
- Entrainment
- synchronization of an internal circadian oscillator to an environmental stimulus that occurs at regular intervals (usually with ∼24 h periodicity).
- Free-running
- the state of a self-sustaining
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