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Understanding systems-level properties: timely stories from the study of clocks

Nature Reviews Genetics volume 12, pages 407–416 (2011)Cite this article

Subjects

Key Points

  • Systems-biology approaches, such as genetic perturbations combined with kinetic luminescence imaging, synthetic-biology approaches and mathematical modelling, are being used to address the complexity of clock function.

  • The circadian clock community has used mouse genetics to establish non-redundant roles for many clock factors that contribute to circadian oscillators that function within cells and in circadian behaviour.

  • Proportionality and paralogue compensation are key principles that convey robustness to the circadian clock.

  • Researchers have exploited the cyanobacterial system to establish that there are oscillations in phosphorylation status in experiments using three proteins (KaiA, KaiB and KaiC) and ATP. The cyanobacterial clock community has leveraged this model to understand the molecular events that establish periodicity as well as concepts such as molecular synchronization. Quantitative and conceptual models have been important in driving this research.

  • 'Traditional' techniques such as genetics can be used to tackle complex issues in clock biology, such as identifying the components and establishing the mechanism for temperature compensation.

Abstract

After several decades dominated by reductionist approaches in biology, researchers are returning to the study of complex biology with a litany of new and old techniques — this paradigm has been termed systems biology. Here we detail how systems biology is being used to uncover complex systems-level properties of the circadian clock. These properties include robustness, periodicity and temperature compensation. We describe how clock researchers are using systems-biology techniques, such as genetic perturbations, kinetic luminescence imaging, synthetic biology and mathematical modelling, to untangle these complex properties in mammals, fungi and bacteria. The strategies developed in the context of circadian clocks may prove useful for tackling similar problems in other systems.

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Figure 1: Perturbation modelling — paralogue compensation and proportionality.
Figure 2: The phosphoform cycle and intermolecular synchronization in cyanobacteria circadian clocks and transcriptional network of mammalian circadian clocks.
Figure 3: The Neurospora crassa circadian clock and two non-exclusive models for temperature compensation.

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Acknowledgements

The authors would like to thank members of the Hogenesch and Ueda laboratories for their comments on this Review. J.B.H. is supported by the National Heart, Lung and Blood Institute (NHBLI, 1R01HL097800), the National Institute for Neurological Disorders and Stroke (NINDS, 5R01NS054794) and the Pennsylvania Commonwealth Health Research Formula Funds. This work was partly supported by the RIKEN research grant and the Cell Innovation Program from MEXT, Japan.

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Authors and Affiliations

  1. Department of Pharmacology, Penn Center for Bioinformatics, Penn Genome Frontiers Institute, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    John B. Hogenesch

  2. Laboratory for Systems Biology, Functional Genomics Unit, Center for Developmental Biology, Laboratory for Synthetic Biology, Quantitative Biology Center, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Hyogo, Japan

    Hiroki R. Ueda

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Correspondence to John B. Hogenesch or Hiroki R. Ueda.

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FURTHER INFORMATION

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Circadian Modelling

Mouse Genome Informatics

Glossary

Temperature compensation

In biological clocks, this is the property by which an increase or decrease in temperature fails to change the period length of the circadian rhythm.

Robustness

The resistance to perturbation by, for example, genetic or environmental factors.

Poikilotherms

Organisms that do not regulate their body temperatures.

Homeotherms

Organisms that regulate their body temperatures.

Bayesian integration

The use of the Bayesian inference — a statistical inference where experimental data is used to infer new or update prior hypotheses — to integrate large-scale, genomic data sets.

Diapause

The suspension of insect development after subjection to adverse environmental conditions.

Rhythmicity

In biological clocks, this is the property by which a molecular, cellular or physiological response recurs with regularity.

RNA interference

(RNAi). A biochemical system in cells that governs how dsRNA can interact with mRNAs to activate or inhibit their message levels or translation.

Autonomous oscillator

In biological clocks, this is a system in which cellular oscillations — rhythmic fluctuations with a definable period length — in gene transcription, reporter gene activity or physiology persist in isolated cells.

Repressilator

This is a synthetic network that generates stable oscillations in GFP.

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Hogenesch, J., Ueda, H. Understanding systems-level properties: timely stories from the study of clocks. Nat Rev Genet 12, 407–416 (2011). https://doi.org/10.1038/nrg2972

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