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Functioning and robustness of a bacterial circadian clock.

ABSTRACT: Cyanobacteria are the simplest known cellular systems that regulate their biological activities in daily cycles. For the cyanobacterium Synechococcus elongatus, it has been shown by in vitro and in vivo experiments that the basic circadian timing process is based on rhythmic phosphorylation of KaiC hexamers. Despite the excellent experimental work, a full systems level understanding of the in vitro clock is still lacking. In this work, we provide a mathematical approach to scan different hypothetical mechanisms for the primary circadian oscillator, starting from experimentally established molecular properties of the clock proteins. Although optimised for highest performance, only one of the in silico-generated reaction networks was able to reproduce the experimentally found high amplitude and robustness against perturbations. In this reaction network, a negative feedback synchronises the phosphorylation level of the individual hexamers and has indeed been realised in S. elongatus by KaiA sequestration as confirmed by experiments.

SUBMITTER: Clodong S

PROVIDER: S-EPMC1847943 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Functioning and robustness of a bacterial circadian clock.

Clodong Sébastien S Dühring Ulf U Kronk Luiza L Wilde Annegret A Axmann Ilka I Herzel Hanspeter H Kollmann Markus M

Molecular systems biology 20070313

Cyanobacteria are the simplest known cellular systems that regulate their biological activities in daily cycles. For the cyanobacterium Synechococcus elongatus, it has been shown by in vitro and in vivo experiments that the basic circadian timing process is based on rhythmic phosphorylation of KaiC hexamers. Despite the excellent experimental work, a full systems level understanding of the in vitro clock is still lacking. In this work, we provide a mathematical approach to scan different hypothe ...[more]

PMID: 17353932

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Project description:BackgroundRobustness 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.ResultsThe 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.ConclusionsOur 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.

Dataset Information

Functioning and robustness of a bacterial circadian clock.

Publications

Functioning and robustness of a bacterial circadian clock.

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