A minimal activator-inhibitor-repressor model to describe the hepatic circadian clock

Abstract

Circadian clocks rely on gene regulation networks which generate periodic biochemical oscillations informing our cells about the time of the day. Mathematical modeling has been effective to describe the dynamics of the multiple intertwined feedback loops making up circadian clocks, however it is often delicate to adapt the complexity of the model to the question addressed and to the data available. Traditionally, two main modeling approaches have been followed, using either comprehensive models recapitulating most molecular actors involved, or minimal qualitative models highlighting the core mechanisms. However, analyzing the behavior of large models may be difficult, and small models often lack predictive power, questioning their relevance. Through a systematic reduction of a more complex model, we obtain a simple three-gene clock model, featuring the activator Bmal1, the repressor Reverb and the inhibitor Cry, that accurately describes the corresponding temporal expression profiles for the mouse hepatic clock. We characterize this model by carrying out a sensitivity analysis for its limit cycle, as well as by computing phase response curves for the different possible inputs. Predictions from the model are compatible with a number of synchronizing mechanisms from the literature. SIGNIFICANCELiving systems adapt to the day/night cycle thanks to cellular clocks, which track the time of the day and orchestrate physiological processes throughout the 24 hours. The dynamics of these clocks is complex, due to the interaction of intertwined feedback loops generating the biochemical oscillations and ensuring their synchronization. Mathematical modeling has proved useful to unravel this complexity, however there is usually a difficult choice to be made between comprehensive and minimal models, with opposite strengths and weaknesses. Here, we propose a simple activator-inhibitor-repressor model reproducing surprinsingly well experimental data from mouse livers, whose analysis casts light on the roles of the main actors of the mammalian circadian clock.