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Robustness from flexibility in the fungal circadian clock.

Akman OE, Rand DA, Brown PE, Millar AJ - BMC Syst Biol (2010)

Bottom Line: Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure.Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator.More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Systems Biology at Edinburgh, The University of Edinburgh, Edinburgh, UK.

ABSTRACT

Background: Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa.

Results: The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq) gene inhibits its transcriptional activator white collar-1 (wc-1), interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure.

Conclusions: Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator. More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators.

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Simulations of the model in different photoperiods. Both frq and wc-1 mRNA exhibit rapid increases in expression at lights-on, while frq mRNA also exhibits a rapid decrease in expression at lights-off, consistent with experimental data [16]. The model also reproduces the convergence of frq and wc-1 to equilibrium levels following dawn in longer photoperiods.
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Figure 3: Simulations of the model in different photoperiods. Both frq and wc-1 mRNA exhibit rapid increases in expression at lights-on, while frq mRNA also exhibits a rapid decrease in expression at lights-off, consistent with experimental data [16]. The model also reproduces the convergence of frq and wc-1 to equilibrium levels following dawn in longer photoperiods.

Mentions: Figures 2 and 3 show simulations of the model in DD and LD conditions respectively. The parameter values used to generate these solutions were obtained by minimising a cost function quantifying the goodness-of-fit of the model to experimental time courses [45-48]. This measured how well simulated solutions matched certain key features of the data, such as the free-running period of the clock and the peak and trough phases of the clock components in both free-running and entrained conditions [46]. The DD simulation has a period close to the observed value of 22 hrs, with relative phase relationships also consistent with experimental data: the delay between the peaks of frq transcript and FRQ protein is approximately 5 hrs, while FRQ and WC-1 protein oscillate roughly in antiphase.


Robustness from flexibility in the fungal circadian clock.

Akman OE, Rand DA, Brown PE, Millar AJ - BMC Syst Biol (2010)

Simulations of the model in different photoperiods. Both frq and wc-1 mRNA exhibit rapid increases in expression at lights-on, while frq mRNA also exhibits a rapid decrease in expression at lights-off, consistent with experimental data [16]. The model also reproduces the convergence of frq and wc-1 to equilibrium levels following dawn in longer photoperiods.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913929&req=5

Figure 3: Simulations of the model in different photoperiods. Both frq and wc-1 mRNA exhibit rapid increases in expression at lights-on, while frq mRNA also exhibits a rapid decrease in expression at lights-off, consistent with experimental data [16]. The model also reproduces the convergence of frq and wc-1 to equilibrium levels following dawn in longer photoperiods.
Mentions: Figures 2 and 3 show simulations of the model in DD and LD conditions respectively. The parameter values used to generate these solutions were obtained by minimising a cost function quantifying the goodness-of-fit of the model to experimental time courses [45-48]. This measured how well simulated solutions matched certain key features of the data, such as the free-running period of the clock and the peak and trough phases of the clock components in both free-running and entrained conditions [46]. The DD simulation has a period close to the observed value of 22 hrs, with relative phase relationships also consistent with experimental data: the delay between the peaks of frq transcript and FRQ protein is approximately 5 hrs, while FRQ and WC-1 protein oscillate roughly in antiphase.

Bottom Line: Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure.Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator.More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Systems Biology at Edinburgh, The University of Edinburgh, Edinburgh, UK.

ABSTRACT

Background: Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa.

Results: The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq) gene inhibits its transcriptional activator white collar-1 (wc-1), interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure.

Conclusions: Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator. More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators.

Show MeSH