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The genetics of mammalian circadian order and disorder: implications for physiology and disease

Key Points

  • Circadian rhythms in mammals are regulated by a master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN), which coordinates rhythmic processes throughout the organism.

  • Circadian clocks are cell autonomous and these cellular clocks are located in SCN neurons as well as in almost every cell in the body.

  • The molecular mechanism of circadian clocks in mammals involves an autoregulatory transcriptional feedback loop involving the positive elements CLOCK and BMAL1, which transcriptionally activate the negative feedback elements period (PER) and cryptochrome (CRY), which inhibit their own transcription by repressing the CLOCK–BMAL1 complex.

  • Post-translational regulation (for example, phosphorylation, acetylation and ubiquitylation) of clock proteins have important roles in regulating the stability, localization and turnover of clock components.

  • The sleep disorder familial advanced sleep phase syndrome (FASPS) has been found to be caused by mutations in two core clock genes, period homologue 2 (PER2) and casein kinase 1 delta (CSNK1D), in humans.

  • There is weak but emerging evidence for allelic variants in clock genes to be associated with diurnal preference, mood disorders, sleep and metabolic disorders.

  • Peripheral circadian oscillators are controlled by signals arising from the SCN and from proximal signals related to feeding behaviour, hormonal signals and body-temperature fluctuations.

  • In addition to their primary role in the generation of circadian rhythms, recent work has shown that circadian clock genes can affect a wide variety of other physiological processes.

  • Emerging examples of circadian regulation of physiological pathways include diverse aspects of cellular metabolism, cell growth and DNA-damage control, xenobiotic responses, and the modulation of behavioural responses to drugs and alcohol.

  • The knowledge that circadian clocks are cell autonomous and distributed throughout the body provide a new perspective to target central as well as peripheral circadian oscillators for therapeutic intervention.

Abstract

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

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Figure 1: A schematic diagram of the suprachiasmatic nucleus and its input and output pathways.
Figure 2: The mammalian circadian clock is composed of a transcriptional–translational feedback network.
Figure 3: Central and peripheral oscillators.
Figure 4: Interactions between circadian and metabolic systems.
Figure 5: Circadian control of cell-division cycles.

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Acknowledgements

We thank the anonymous reviewers for their editorial suggestions. Research is supported by grants from the National Institutes of Health (U01 MH61915 and R01 MH078024) and a Silvio O. Conte Center grant (P50 MH074924) to J.S.T. J.S.T. is an Investigator in the Howard Hughes Medical Institute.

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Correspondence to Joseph S. Takahashi.

Supplementary information

Supplementary information S1 (table)

Human circadian gene mutation and associated phenotypic effects/disorders. (PDF 0 kb)

Supplementary information S2 (table)

Mouse circadian mutants and observed circadian and physiological phenotypes. (PDF 164 kb)

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DATABASES

OMIM

delayed sleep phase syndrome

familial advanced sleep-phase syndrome

FURTHER INFORMATION

Joseph S. Takahashi at Northwestern University

Joseph S. Takahashi at Howard Hughes Medical Institute

Clockwork Genes, HHMI's BioInteractive

Glossary

Suprachiasmatic nucleus

(SCN). The master circadian pacemaker in the mammalian brain, which is composed of a group of neurons located in the anterior hypothalamus immediately dorsal to the optic chiasm.

Retinal ganglion cells

A class of neuronal cells in the mammalian retina that relay information to the central nervous system via the optic tracts.

Sleep homeostatic process

A formal description of a control process underlying the drive to sleep, typically estimated from the intensity of slow-wave sleep as measured from the Fourier spectrum of electroencephagram recordings from the brain.

Narcolepsy

A sleep disorder characterized by sleepiness, cataplexy and abnormal transitions from wakefulness into rapid eye movement sleep.

Hyperphagia

Excessive eating.

Arcuate nucleus

A group of neurons in the mediobasal hypothalamus of the brain that are involved in a number of neuroendocrine functions and feeding.

Hyperlipidaemia

Elevation of lipids (fats) in the bloodstream.

Hepatic steatosis

Fatty liver.

Hyperglycaemia

Elevation of glucose in the bloodstream.

Hypoinsulinaemia

Abnormally low insulin in the bloodstream.

Sarcopaenia

Age-related loss of skeletal muscle mass and strength.

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Takahashi, J., Hong, HK., Ko, C. et al. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9, 764–775 (2008). https://doi.org/10.1038/nrg2430

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