Mathematical modeling of an oscillating gene circuit to unravel the circadian clock network of Arabidopsis thaliana

The Arabidopsis thaliana circadian clock is an interconnected network highly tractable to systems approaches. Most elements in the transcriptional–translational oscillator were identified by genetic means and the expression of clock genes in various mutants led to the founding hypothesis of a positive–negative feedback loop being the core clock. The identification of additional clock genes beyond those defined in the core led to the use of systems approaches to decipher this angiosperm oscillator circuit. Kinetic modeling was first used to explain periodicity effects of various circadian mutants. This conformed in a flexible way to experimental details. Such observations allowed a recursive use of hypothesis generating from modeling, followed by experimental corroboration. More recently, the biochemical finding of new description of a DNA-binding activity for one class of clock components directed improvements in feature generation, one of which revealed that the core of the oscillator is a negative–negative feedback loop. The recursive use of modeling and experimental validation has thus revealed many essential transcriptional components that drive negative arms in the circadian oscillator. What awaits is to more fully describe the positive arms and an understanding of how additional pathways converge on the clock.