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A clockwork web: circadian timing in brain and periphery, in health and disease

Key Points

  • Circadian rhythms are daily cycles of physiology and behaviour that are driven by an endogenous oscillator with a period of approximately (circa-) one day (diem). Exemplified in humans by the rhythm of sleep and wakefulness and their attendant neurophysiological and metabolic states, they are a pervasive feature of eukaryotes, enabling the organism to anticipate and thereby adapt to the solar cycle.

  • In mammals, the principal oscillator is the suprachiasmatic nuclei (SCN) of the hypothalamus. The circadian timing mechanism is cell-autonomous and is expressed individually by SCN neurons. Synchrony across the SCN neuronal network is maintained by γ-aminobutyric acid (GABA) and peptide signalling. It is entrained to the light–dark cycle by glutamatergic retinal afferents, derived in part from a class of intrinsically photosensitive, melanopsin-positive retinal ganglion cells.

  • The cellular oscillator consists of interlocked transcriptional and post-translational feedback loops. Heterodimeric complexes encoded by the Clock and Bmal genes drive expression of Per and Cry genes during circadian day, leading to accumulation of Per/Cry protein complexes that enter the nucleus and suppress transcription of their cognate genes, thereby establishing an oscillatory negative feedback loop. A feedforward loop, mediated by rhythmic expression of Rev-erbα, phases the expression of Bmal to circadian night, in antiphase to Per and Cry, thereby augmenting the core oscillation.

  • This SCN cycle is synchronized to solar time by neurochemical cues that activate or suppress Per expression. Circadian organization within and beyond SCN neurons is mediated by rhythmic expression of clock-controlled genes that sit outside the feedback loop, but undergo periodic transcriptional activation and repression by Per, Cry and Rev-erbα.

  • Circadian oscillators based on rhythmic Per gene expression are also present in non-neural, peripheral tissues and immortalized cell lines. They have tissue-specific variations in molecular composition and coordinate the local, tissue-specific temporal patterns of gene expression that underpin circadian metabolic programmes.

  • As with the SCN oscillator, where up- and down-regulation of Per resets circadian time, these peripheral oscillators can be reset or activated by various biochemical cues that acutely regulate Per expression. In vivo, this resonant network of peripheral oscillators is synchronized by behavioural, neural, endocrine and food-related cues that depend on the SCN. Manipulation of these cues in vivo can desynchronize peripheral oscillators from the SCN.

  • Circumstances that disrupt the smooth temporal integration of metabolism within and between tissues impose a burden on health. Therapeutic managements should be designed to maintain circadian structure in the periphery. Circadian prevalence of chronic disease is a reflection of the activity of peripheral oscillators and their interactions. Targeted modification of these local endogenous clocks should provide avenues for selective and specific treatment. The contribution of circadian mechanisms to tumour progression highlights the value of incorporating and exploiting temporal specificity in therapeutic regimes.

Abstract

The hypothalamic suprachiasmatic nuclei (SCN) are our principal circadian oscillator, coordinating daily cycles of physiology and behaviour that adapt us to the world. Local versions of the SCN clockwork are also active in peripheral, non-neural tissues, driving the tissue-specific cycles of gene expression that underpin circadian organization. These local oscillators are tuned to each other, and to solar time, by neuroendocrine and metabolic cues that depend on the SCN. The discovery of these local circadian clocks forces a re-appraisal of established models of circadian biology. It also presents new avenues for therapeutic intervention in conditions where disturbance of circadian gene expression is an important cause of morbidity.

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Figure 1: A brief history of circadian time.
Figure 2: The molecular feedback loops that define circadian time.
Figure 3: Per::luciferase transgenes reveal a diversity of tissue-based circadian oscillators.
Figure 4: Peripheral circadian clocks in cardiovascular disease.

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Acknowledgements

The authors' work is supported by the Medical Research Council, UK. They are very grateful to M. Hansen and P. Redfern for providing the detail of J. Wren's Herbal.

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Correspondence to Michael H. Hastings.

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DATABASES

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Bmal1

Clock

Cry

Pai1

Per

Rev-erbα

slimb

VPAC2

OMIM

Alzheimer disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

circadian rhythms

Glossary

CIRCADIAN DAY/CIRCADIAN NIGHT

A notation of biological time, applied when organisms are in temporal isolation, devoid of external timing cues. The full circadian cycle is divided into 24 circadian hours, with circadian time (CT) 0 corresponding to subjective dawn, and CT12 subjective dusk. For nocturnal rodents, therefore, the onset of locomotor activity at CT12 marks the start of circadian night.

bHLH-PAS PROTEINS

Transcription factors characterized by a basic helix–loop–helix (bHLH) motif that facilitates DNA-binding and dimerization, and PAS protein–protein interaction domains that facilitate formation of heterodimeric complexes. They are characteristically involved in developmental events and adaptation to the environment.

RORE DNA SEQUENCES

Regulatory DNA sequences that are a target for retinoic acid receptor-related orphan receptors (ROR) — nuclear proteins with homology to retinoic acid receptors. The typical ROR element in the circadian system has the nucleotide sequence AGGTCA.

DNA E-BOX SEQUENCES

Regulatory DNA sequences that enhance transcription by providing a target for transcription factors, including bHLH-PAS proteins. They are involved in cell division, differentiation and apoptosis. The typical E-box in the circadian system has the nucleotide sequence CACGTG.

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Hastings, M., Reddy, A. & Maywood, E. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 4, 649–661 (2003). https://doi.org/10.1038/nrn1177

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