Switching, Multiple Time-Scales and Geometric Blow-Up in a Low-Dimensional Gene Regulatory Network

Abstract

ODE-based models for gene regulatory networks (GRNs) can often be formulated as smooth singular perturbation problems with multiple small parameters, some of which are related to time-scale separation, whereas others are related to 'switching' (proximity to a non-smooth singular limit). This motivates the study of reduced models obtained after (i) quasi-steady state reduction (QSSR), which utilises the time-scale separation, and (ii) piecewise-smooth approximations, which reduce the nonlinearity of the model by viewing highly nonlinear sigmoidal terms as singular perturbations of step functions. We investigate the interplay between the reduction methods (i)-(ii), in the context of a 4-dimensional GRN which has been used as a low-dimensional representative of an important class of (generally high-dimensional) GRN models in the literature. We begin by identifying a region in the small parameter plane for which this problem can be formulated as a smooth singularly perturbed system on a blown-up space, uniformly in the switching parameter. This allows us to apply Fenichel's coordinate-free theorems and obtain a rigorous reduction to a 2-dimensional system, that is a perturbation of the QSSR. Finally, we show that the reduced system features a Hopf bifurcation which does not appear in the QSSR system, due to the influence of higher order terms. Taken together, our findings suggest that the relative size of the small parameters is important for the validity of QSS reductions and the determination of qualitative dynamics in GRN models more generally. Although the focus is on the 4-dimensional GRN, our approach is applicable to higher dimensions.