Robustness from flexibility in the fungal circadian clock

Abstract

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.

A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery

“…S6). A similar topology appears in other rhythmic systems, and a recent analysis indicates that an embedded positive feedback loop has advantages for the precision and robustness of negative feedback oscillators (36). It is likely that circadian rhythms of physiology and behavior rely on fine temporal control of transcription within and beyond the circadian clock feedback loop (37).…”

Period Coding of Bmal1 Oscillators in the Suprachiasmatic Nucleus

“…However, it has not been defined precisely how each heterodimeric combination of PER1, 2, 3, and CRY1, 2 coordinates feedback to Bmal1 expression (Reppert and Weaver, 2002). Functionally, relative independence of the positive-and negative-feedback loops can enable cellular coding of the day length as suggested by the computational model of the fungal circadian clock (Akman et al, 2010). We speculate that the difference in susceptibility to outside influence of the two loops (von Gall et al, 2003) could be one factor that led to different behaviors of Bmal1-ELuc and PER2::LUC.…”

LIGHT-REGULATED WD1 and PSEUDO-RESPONSE REGULATOR9 Form a Positive Feedback Regulatory Loop in the Arabidopsis Circadian Clock

“…Negative feedback loops can contribute to the clock's function in building the 24-h oscillation. However, mathematical modeling suggested that in Neurospora, a positive loop could enhance the buffering of the conidiation phase against seasonal photoperiod changes (Akman et al, 2010). Successful integration of positive and negative feedback loops are known to play key roles in maintaining the stability and robustness of the oscillator in Neurospora (Lee et al, 2000;Cheng et al, 2001).…”