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Clocks not winding down: unravelling circadian networks

Key Points

  • Using combined approaches of genetics, biochemistry, molecular biology and functional genomics, the field of circadian biology has identified hundreds of new clock genes and modifiers during the past decade.

  • Our understanding of the clock mechanism has advanced from a simple transcriptional–translational feedback loop to a extensive networks. These networks are composed of multiple regulatory layers ranging from transcriptional circuits to protein modifications, small molecule feedback and systemic control of the whole organism.

  • Mathematical modelling and synthetic approaches provide useful tools to reconstruct clock networks, generate simulations, and predict outcomes of designed experiments. Features of circadian network structure and essential properties have been elucidated.

  • The clock provides adaptive advantage to organisms, such as benefits to plants from using energy sources efficiently and conferring enhanced fitness in day–night cycles.

  • Human physiology and metabolic homeostasis are tightly regulated by the clock. Malfunctions of the clock cause various human diseases such as sleep disorders and metabolic syndromes, and pharmaceutical manipulation of circadian attributes may provide a new way to treat these diseases.

  • Future studies combining structural biology, chemical biology, systems and synthetic biology will broaden our knowledge of circadian rhythms.

Abstract

An intrinsic clock enables an organism to anticipate environmental changes and use energy sources more efficiently, thereby conferring an adaptive advantage. Having an intrinsic clock to orchestrate rhythms is also important for human health. The use of systems biology approaches has advanced our understanding of mechanistic features of circadian oscillators over the past decade. The field is now in a position to develop a multiscale view of circadian systems, from the molecular level to the intact organism, and to apply this information for the development of new therapeutic strategies or for enhancing agricultural productivity in crops.

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Figure 1: Historical perspectives on understanding mammalian clock genes.
Figure 2: Conceptual modelling of clock gene circuits in different organisms.
Figure 3: Reciprocal regulation of the circadian and metabolic networks.
Figure 4: Loops surrounded by loops: whole organism oscillations in humans.

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Acknowledgements

We apologize to all colleagues whose work cannot be cited owing to space limitations. We thank D. Welsh and members of the Kay laboratory for critical readings of the manuscript. S.A.K is supported by grants from US National Institutes of Health (R01 MH051573, R01 GM074868, RO1 GM056006, RO1 GM067837 and RO1 GM092412.).

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Correspondence to Steve A. Kay.

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Eric E. Zhang and Steve A. Kay

Steve A. Kay is a cofounder of ReSet Therapeutics and is a member of its scientific advisory board.

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Circadian BioGPS database

Glossary

Long-period

A mutant organism that shows, in the absence of environmental signals such as light and temperature, an endogenous period of more than 24 hours when assayed by behaviour or physiology.

Short-period

A mutant organism that shows, in the absence of environmental signals such as light and temperature, an endogenous period of less than 24 hours when assayed by behaviour or physiology.

Arrhythmic

A mutant organism that, in the absence of environmental signals such as the light and temperature, shows no clear daily pattern when assayed by behaviour or physiology.

Eclosion

Hatching of an insect larva from an egg or the emergence of an adult insect from its pupal case.

Suprachiasmatic nucleus

A small region in the hypothalamus of the brain, consisting of roughly 10,000–20,000 neurons. Also known as the master clock in mammals.

Robustness

A parameter used to describe the characteristics of an oscillator that is resilient to intrinsic or extrinsic perturbations.

Entrainment

Alignment of period or phase of an endogenous clock system to its counterpart of an external rhythm.

Period

Time difference between two neighbouring peaks of a clock oscillation wave.

Amplitude

Magnitude change between the peak- and trough-points of a clock oscillation wave.

Phase

Initial angle of a clock oscillation wave.

E-box

A short DNA element that binds to transcription factors CLOCK–BMAL1. The canonical sequence of an E-box is CACGTG. An element with the non-canonical sequence CACGTT is named E′-box and is found in promoters of some CLOCK–BMAL1-regulated genes such as Per2.

Nuclear receptor

Also known as nuclear hormone receptor; upon association with hormone ligands, these receptors enter nuclei and bind to sequence-specific DNA fragments to activate the transcription of specific genes.

Histone methyltransferase

An enzyme that catalyses the transfer of a methyl group to Lys and/or Arg residues in histones; the most well-studied histone methyltransferase is Su(var)3-9 and its mammalian homologues, which methylate histone H3 on Lys9.

Class III histone deacetylase

A subgroup of histone deacetylases (HDACs), which are enzymes that remove the acetyl group from Lys in histones. Members of class III HDACs include sirtuin in the yeast Saccharomyces cerevisiae and its mammalian homologues.

Yeast one-hybrid screen

A genetic assay for identifying and characterizing new protein–DNA interactions.

TCP transcription factor

A family of transcription factors that contain the TCP (TB1, CYC and PCFs) domain, which are involved in regulating growth and development in plants.

F-box protein

A protein that contains the F-box motif, which comprises 50 amino acid residues and is involved in mediating protein–protein interactions. F-box proteins are usually involved in ubiquitin-mediated protein degradation.

Pigment-dispersing factor

A neuropeptide that mediates the synchronization among clock neurons in D. melanogaster.

Locomotor rhythmicity

An animal's moving behaviours that display periodical patterns.

N-ethyl-N-nitrosourea

A highly potent chemical used to generate mutant mice.

Kai proteins

Members of the bacterial RecA/DnaB superfamily, which are ATP-dependent DNA recombinases and replication fork helicases.

RRE

A short DNA element that associates with REV–ERBα, REV–ERBβ and ROR. The common sequence of a RRE is (A/T)A(A/T)NT(A/G)GGTCA.

D-box

A short DNA element that associates with transcription factors such as DBP. The common sequence of a D-box is TTATG(C/T)AA.

Gene dosage analysis

An assay to functionally analyse the disturbed expression of individual and combinations of network components in a dose-dependent manner, using approaches such as co-transfection of controlled amount of cDNA or RNAi.

Feed-forward loop

An element or pathway in a control system that passes a controlling signal from a source in the control system's external environment, often a command signal from an external operator, to a load elsewhere in its external environment.

Rod cell

A photoreceptor cell in the mammalian eyes that senses dim light.

Cone cell

A photoreceptor cell in the mammalian eyes that senses strong light.

Xenobiotic metabolism

A group of metabolic reactions that modify the structures of exogenous chemicals or small molecules.

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Zhang, E., Kay, S. Clocks not winding down: unravelling circadian networks. Nat Rev Mol Cell Biol 11, 764–776 (2010). https://doi.org/10.1038/nrm2995

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