Deciphering the Dynamics of Interlocked Feedback Loops in a Model of the Mammalian Circadian Clock.

Mathematical models of fundamental biological processes play an important role in consolidating theory and experiments, especially if they are systematically developed, thoroughly characterized, and well tested by experimental data. In this work, we report a detailed bifurcation analysis of a mathematical model of the mammalian circadian clock network developed by Relógio et al., noteworthy for its consistency with available data. Using one- and two-parameter bifurcation diagrams, we explore how oscillations in the model depend on the expression levels of its constituent genes and the activities of their encoded proteins. These bifurcation diagrams allow us to decipher the dynamics of interlocked feedback loops by parametric variation of genes and proteins in the model. Among other results, we find that REV-ERB, a member of a subfamily of orphan nuclear receptors, plays a critical role in the intertwined dynamics of Relógio's model. The bifurcation diagrams reported here can be used for predicting how the core clock network responds-in terms of period, amplitude and phases of oscillations-to different perturbations.