Location of Repository

Robustness from flexibility in the fungal circadian clock

By Ozgur E. Akman, D. A. (David A.) Rand, Paul E. Brown and A. J. (Andrew J.) Millar


Background\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusions\ud 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.\u

Topics: QK, QP
Publisher: BioMed Central Ltd.
Year: 2010
OAI identifier: oai:wrap.warwick.ac.uk:3343

Suggested articles



  1. (2005). A model for the Neurospora circadian clock. doi
  2. (1999). A: Limit cycle models for circadian rhythms based on transcriptional regulation in Drosophila and Neurospora. doi
  3. (2005). AA: Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science
  4. (2004). AJ: Design principles underlying circadian clocks. doi
  5. (2006). AJ: Uncovering the design principles of circadian clocks: mathematical analysis of flexibility and evolutionary goals. doi
  6. (1989). Biological Delay Systems: Linear Stability Theory Cambridge, doi
  7. (2004). Biological robustness. Nat Rev Genet doi
  8. (1998). CH: Resonating circadian clocks enhance fitness in cyanobacteria. doi
  9. (2005). Circuit topology and the evolution of robustness in two-gene circadian oscillators. doi
  10. (2008). Closing the circadian negative feedback loop: FRQ-dependent clearance of WC-1 from the nucleus. Genes Dev doi
  11. (2001). Coiled-coil domain-mediated FRQFRQ interaction is essential for its circadian clock function in Neurospora. doi
  12. (2007). Complexity of the Neurospora crassa circadian clock system: multiple loops and oscillators. Cold Spring Harb Symp Quant Biol doi
  13. (2006). D: The rhythms of life: circadian output pathways in Neurospora. doi
  14. (2008). DA: Isoform switching facilitates period control in the Neurospora crassa circadian clock. Mol Syst Biol doi
  15. (2007). Doyle FJ: Quantitative performance metrics for robustness in circadian rhythms. Bioinformatics doi
  16. (2001). Ebbole DJ: vvd is required for light adaptation of conidiation-specific genes of Neurospora crassa, but not circadian conidiation. Fungal Genet Biol doi
  17. (2004). Entrainment dissociates transcription and translation of a circadian clock gene in Neurospora. Curr Biol doi
  18. (2007). FJ: Phase sensitivity analysis of circadian rhythm entrainment. doi
  19. (2004). FJ: Robustness properties of circadian clock architectures. doi
  20. (2001). Genetic and molecular analysis of circadian rhythms in Neurospora. Annu Rev Physiol doi
  21. (2002). Goldbeter A: Biochemical clocks and molecular noise: theoretical study of robustness Factors. doi
  22. (2002). Goldbeter A: Robustness of circadian rhythms with respect to molecular noise. doi
  23. (2003). Goldbeter A: Toward a detailed computational model for the mammalian circadian clock. doi
  24. (2004). Gopinathan MS: A two variable delay model for the circadian rhythm of Neurospora crassa. doi
  25. (2005). Heintzen HC: The PAS/LOV protein VIVID supports a rapidly dampened daytime oscillator that facilitates entrainment of the Neurospora circadian clock. Genes Dev doi
  26. (2005). III: A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9. Mol Syst Biol doi
  27. (2000). Interconnected feedback loops in the Neurospora circadian system. Science doi
  28. (2001). Interlocked feedback loops contribute to the robustness of the Neurospora circadian clock. doi
  29. (2002). Iwasa Y: Comparative study of circadian clock models, in search of processes promoting oscillation. doi
  30. (2002). Iwasa Y: Saturation of enzyme kinetics in circadian clock models. doi
  31. (1997). JC: Alternative initiation of translation and time-specific phosphorylation yield multiple forms of the essential clock protein FREQUENCY. Cell doi
  32. (1995). JC: Light-induced resetting of a circadian clock is mediated by a rapid increase in frequency transcript. Cell doi
  33. (2003). JC: Rhythmic binding of a WHITE COLLARcontaining complex to the frequency promoter is inhibited by FREQUENCY. doi
  34. (2005). JC: Temperature-modulated alternative splicing and promoter use in the circadian clock gene frequency. Mol Biol Cell doi
  35. (2001). JC: The PAS protein VIVID defines a clockassociated feedback loop that represses light input, modulates gating, and regulates clock resetting. Cell doi
  36. (2005). JC: The relationship between FRQ-protein stability and temperature compensation in the Neurospora circadian clock. doi
  37. (2001). JC: WC-2 mediates WC1-FRQ interaction within the PAS protein-linked circadian feedback loop of Neurospora. doi
  38. (2003). JH: Reduced models of the circadian oscillators in Neurospora crassa and Drosophila melanogaster illustrate mechanistic similarities. OMICS doi
  39. (2009). Jr: Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science doi
  40. (2001). Kitano H: Robust oscillations within the interlocked feedback model of Drosophila circadian rhythm. doi
  41. (2002). Light and clock expression of the Neurospora clock gene frequency is differentially driven by but dependent on WHITE-COLLAR-2. Genetics
  42. (2008). Mapping global sensitivity of cellular network dynamics: sensitivity heat maps and a global summation Law. doi
  43. (2006). Millar AJ: Experimental validation of a predicted feedback loop in the multi-oscillator clock of Arabidopsis thaliana. Mol Syst Biol doi
  44. (2005). Millar AJ: Extension of a genetic network model by iterative experimentation and mathematical analysis. Mol Syst Biol doi
  45. (2005). Molecular mechanism of temperature sensing by the circadian clock of Neurospora crassa. Genes Dev doi
  46. (2005). MS: Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana. doi
  47. (1983). Nonlinear Oscillations, Dynamical Systems and Bifurcations of Vector Fields doi
  48. (1998). Perelson AS: Influence of delayed viral production on viral dynamics in HIV-1 infected patients. Math Biosci doi
  49. (2006). Phosphorylationdependent maturation of Neurospora circadian clock protein from a nuclear repressor toward a cytoplasmic activator. Cell doi
  50. (2003). PJ: Chronobiology: Biological TimeKeeping
  51. (2005). Regulation of the Neurospora circadian clock by an RNA helicase. Genes Dev doi
  52. (1999). Roenneberg T: Assignment of circadian function for the Neurospora clock gene frequency. Nature
  53. (2001). Roenneberg T: Circadian regulation of the light input pathway in Neurospora crassa. doi
  54. (2006). Roenneberg T: Entrainment of the Neurospora circadian clock. Chronobiol Int doi
  55. (2001). SA: Time zones: a comparative genetics of circadian clocks. Nat Rev Genet
  56. (2003). Sethna JP: Statistical mechanical approaches to models with many poorly known parameters. Phys Rev E doi
  57. (2007). Sethna JP: Universally sloppy parameter sensitivities in systems biology models. PLoS Comput Biol doi
  58. (2008). Simulating dark expressions and interactions of frq and wc-1 in the Neurospora circadian clock. doi
  59. Studies of the circadian clock of Neurospora crassa: light-induced phase shifting. doi
  60. (2001). The Neurospora circadian clock: simple or complex?
  61. (2007). Towards a theory of biological robustness. doi
  62. (2005). Transcriptional feedback of Neurospora circadian clock gene by phosphorylation-dependent inactivation of its transcription factor. Cell doi
  63. (2003). VIVID is a flavoprotein and serves as a fungal blue light photoreceptor for photoadaptation. doi
  64. (2002). White collar-1, a circadian blue light photoreceptor, binding to the frequency promoter. Science doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.