Effects of coupling strength and space on the dynamics of coupled toggle switches in stochastic gene networks with multiple-delayed reactions

Genetic toggle switches (TSs) are one of the best studied small gene regulatory networks (GRNs), due to their simplicity and relevant role. They have been interpreted as decision circuits in cell differentiation, a process long hypothesized to be bistable [1], or as cellular memory units [2]. In these contexts, they must be reliable. Once a decision is made, the system must remain stable. One way to gain stability is by duplicating the genes of a TS and coupling the two TSs. Using a recent modeling strategy of GRNs, driven by a delayed stochastic simulation algorithm (delayed SSA) that allows modeling transcription and translation as multidelayed reactions, we analyze the stability of systems of coupled TSs. For this, we introduce the coupling strength (C), a parameter to characterize the GRN structure, against which we compare the GRN stability (S). We first show that time delays in transcription, associated to the promoter region release, ensure bistability of a TS, given no cooperative binding or self-activation reactions. Next, we couple two TSs and measure their toggling frequencies as C varies. Three dynamical regimes are observed: (i) for weak coupling, high frequency synchronized oscillations, (ii) for average coupling, low frequency synchronized oscillations, and (iii) for strong coupling the system becomes stable after a transient, in one of two steady states. The system stability, S, goes through a first order phase transition as C increases, in the average coupling regime. After, we study the effects of spatial separation in two compartments on the dynamics of two coupled TSs, where spatial separation is modeled as normally distributed random time delayed reactions. The phase transition of S, as C increases, occurs for lower values of C than when the two TSs are in the same compartment. Finally, we couple weakly and homogeneously several TSs within a single compartment and observe that as the number of coupled TSs increases, the system goes through the phase transition in S, from oscillatory to stable and for C values lower than in the two previous cases.