Mathematical modeling and validation of glucose compensation of the Neurospora circadian clock

Abstract

Autonomous circadian oscillations arise from transcriptional-translational feedback loops of core clock components. The period of a circadian oscillator is relatively insensitive to changes in nutrients (e.g., glucose), which is referred to as "nutrient compensation". Recently, a transcription repressor, CSP-1, was identified as a component of the circadian system in Neurospora crassa. The transcription of csp-1 is under the circadian regulation. Intriguingly, CSP-1 represses the circadian transcription factor, WC-1, forming a negative feedback loop that can influence the core oscillator. This feedback mechanism is suggested to maintain the circadian period in a wide range of glucose concentrations. In this report, we constructed a mathematical model of the Neurospora circadian clock incorporating the above WC-1/CSP-1 feedback loop, and investigated molecular mechanisms of glucose compensation. Our model shows that glucose compensation exists within a narrow range of parameter space where the activation rates of csp-1 and wc-1 are balanced with each other, and simulates loss of glucose compensation in csp-1 mutants. More importantly, we experimentally validated rhythmic oscillations of the wc-1 gene expression and loss of glucose compensation in the wc-1 ov mutant as predicted in the model. Furthermore, our stochastic simulations demonstrate that the CSP-1-dependent negative feedback loop functions in glucose compensation, but does not enhance the overall robustness of oscillations against molecular noise. Our work highlights predictive modeling of circadian clock machinery and experimental validations employing Neurospora and brings a deeper understanding of molecular mechanisms of glucose compensation.