Self-Activation Attenuates the Adverse Effects of Scarce Resources on Genetic Switches

The limited availability of shared cellular resources introduces strong coupling among seemingly unrelated components. Given the fundamental role that multistable switches play in both natural and synthetic genetic systems, here we focus on how the scarcity of resources affects the behavior of these elementary building blocks. In particular, we reveal that while competition for scarce resources pushes the dynamics towards monostability, self-activation attenuates this phenomenon, as well as perturbations from the genetic context of the switch. However, this robustness comes at a price: our analysis uncovers that strong self-activation can lead to tristable dynamics that can surprisingly and misleadingly appear as if the underlying system was monostable, especially when considering cell-to-cell heterogeneity. This letter thus exposes how self-activation and competition for scarce resources establish the stability and robustness properties of genetic switches at both single cell and population levels. Due to their analytic nature, our results provide explicit guidelines for the rational and optimal design of synthetic gene circuits and facilitate the analysis of organizing principles underlying natural systems.