Vilar, Kueh, Barkai, Leibler, 2002

Model Status

This model has been curated and is known to run in PCEnv and reproduce the results published in the paper on which it is based.

Model Structure

In order to adapt to the the environment's daily cycles of light and dark many organisms, from cyanobacteria to mammals have evolved circadian rhythms. These biological clocks have a period of about 24 hours and they regulate physiological and behavioural processes to best suit different times of the day. Recent studies have shown that these clocks in different species share similar underlying molecular mechanisms, suggesting that they could be evolutionarily ancient and conserved (homologous). The main common feature is the presence of gene transcription regulation networks which give rise to the gene expression oscillations. A positive element activates genes coupled to a circadian clock, simultaneously promoting the expression of a negative element, which in turn represses the positive element (negative feedback inhibition). When the negative element is degraded the cycle completes itself and the positive element is re-expressed.

An essential feature of circadian clocks is to maintain a constant period in spite of fluctuations in the internal and external environments. Such robustness ensures that the clock runs accurately and that clock-dependent genes are expressed at the appropriate time of the day. Potential disturbances include:

  • fluctuations in temperature which may affect the rate of biochemical reactions;

  • internal noise caused by the stochastic nature of biochemical reactions; and

  • low numbers of molecules may generate random fluctuations that can destabilise the oscillatory network.

Yet circadian clocks maintain a fairly constant period.

In order to better understand the potential molecular mechanisms underlying circadian clocks, Vilar et al. developed a mathematical model of a genetic oscillator (see the figure below). The model involves two genes, an activator A and a repressor R, which are transcribed into mRNA and then translated into protein. If the two proteins bind to each other, they form an inactivated complex, C. The activator A binds to the promoter regions of both the A and R genes, which has the effect of increasing their transcription rate. Thus A acts as the positive element in transcription while R acts as the negative element by sequestering the activator.

Model simulations suggest that the oscillations are driven by two components, a repressor protein and an activator-repressor complex. The clock doesn't rely on mRNA dynamics to oscillate which makes it especially resistant to environmental fluctuations. In fact, under certain conditions, this oscillator is not only resistant to, but also enhanced by the background biochemical noise.

The complete original paper reference is cited below:

Mechanisms of noise-resistance in genetic oscillators, Jose M. G. Vilar, Hao Yuan Kueh, Naama Barkai, and Stanislas Leibler, 2002, Proceedings of the National Academy of Sciences of the United States of America , 99, 5988-5992. (Full text (HTML) and PDF versions of the article are available on the Proceedings of the National Academy of Sciences of the United States of America website.) PubMed ID: 11972055

Biochemical network of the circadian oscillator model.
Source
Derived from workspace Vilar, Kueh, Barkai, Leibler, 2002 at changeset c527582b3826.
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