Robust and Tunable Toggle Switches with Interlocked Positive Feedback Loops

Abstract

Toggle switches are widely used to make critical all-or-none decisions such as cell differentiation or apoptosis. While the toggle switch can be generated by using a single-type positive feedback loop (PFL), a natural toggle switch frequently emerges from interlocked PFLs composed of two different types of PFLs: one with two mutually activated units and the other with two mutually inhibiting units. To investigate the advantage of the interlocked PFL over the single type of PFL, here, we carefully analyze how the interlocked PFLs generate bistability and thus the toggle switch. We find that in the interlocked PFLs, mutual activation and mutual inhibition cooperate to generate a robust merged bistability. Interestingly, we also find that turning-on and turning-off of the merged bistability can be flexibly controlled by using the balance between the strengths of two competing PFLs. We illustrate the role of such robust and tunable joint toggle switches of the interlocked PFLs in the DNA damage checkpoint control of G2/M transition. Our work describes how natural toggle switches achieve two critical properties, robustness and tunability, simultaneously by merging opposite types of PFLs.