Modeling circadian clocks: Roles,advantages, and limitations

Circadian rhythms are endogenous oscillations characterized by a period of about 24h. They constitute the biological rhythms with the longest period known to be generated at the molecular level. The abundance of genetic information and the complexity of the molecular circuitry make circadian clocks a system of choice for theoretical studies. Many mathematical models have been proposed to understand the molecular regulatory mechanisms that underly these circadian oscillations and to account for their dynamic properties (temperature compensation, entrainment by light dark cycles, phase shifts by light pulses, rhythm splitting, robustness to molecular noise, intercellular synchronization). The roles and advantages of modeling are discussed and illustrated using a variety of selected examples. This survey will lead to the proposal of an integrated view of the circadian system in which various aspects (interlocked feedback loops, inter-cellular coupling, and stochasticity) should be considered together to understand the design and the dynamics of circadian clocks. Some limitations of these models are commented and challenges for the future identified.