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.

Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator

“…Note, that modified Goodwin oscillators with additional nonlinearities allow reductions of the Hill coefficient as well [43, 44]. Generally, systems with multiple nonlinearities and delayed feedbacks allow robust oscillations with reasonable Hill coefficients [32, 45, 46]. The repressilator motif allows to distribute nonlinearities and delays.…”

An inactivation switch enables rhythms in aNeurosporaclock model

“…It has been found experimentally that the Neurospora clock keeps its period almost constant at varying temperatures and glucose concentrations [68,69]. In a previous study an auxiliary transcriptional feedback loop has been postulated for glucose compensation [70].…”

“…Therefore, they utilize compensation mechanisms against the changes in temperature and nutrients (glucose), where changes in these environmental signals do not affect the overall clock period. There are suggested temperature compensation mechanisms [68,69] and glucose compensation via an auxiliary feedback [70].…”

Bayesian Modeling Reveals Ultrasensitivity Underlying Metabolic Compensation in the Cyanobacterial Circadian Clock

“…We note here that the ultrasensitivity in KaiC phosphorylation that we discovered acts to regulate KaiA activity at a different phase of the cycle than the ultrasensitivity in KaiB-dependent KaiA sequestration that arises from opposing S and T phosphorylations within hexamers (Lin et al, 2014). Presumably, the presence of nonlinearities and delayed feedback at multiple steps in a molecular oscillator allows the system to achieve greater robustness (Kim and Forger, 2012; Jolley et al, 2012; Dovzhenok et al, 2015; Pett et al, 2016).…”