Interlinking positive and negative feedback loops creates a tunable motif in gene regulatory networks

Abstract

Positive and negative feedback loops are often coupled to perform various functions in gene regulatory networks, acting as bistable switches, oscillators, and excitable devices. It is implied that such a system with interlinked positive and negative feedback loops is a flexible motif that can modulate itself among various functions. Here, we developed a minimal model for the system and systematically explored its dynamics and performance advantage in response to stimuli in a unifying framework. The system indeed displays diverse behaviors when the strength of feedback loops is changed. First, the system can be tunable from monostability to bistability by increasing the strength of positive feedback, and the bistability regime is modulated by the strength of negative feedback. Second, the system undergoes transitions from bistability to excitability and to oscillation with increasing the strength of negative feedback, and the reverse conversion occurs by enhancing the strength of positive feedback. Third, the system is more flexible than a single feedback loop; it can produce robust larger-amplitude oscillations over a wider stimulus regime compared with a single time-delayed negative feedback loop. Furthermore, the tunability of the system depends mainly on the topology of coupled feedback loops but less on the exact parameter values or the mode of interactions between model components. Thus, our results interpret why such a system represents a tunable motif and can accomplish various functions. These also suggest that coupled feedback loops can act as toolboxes for engineering diverse functional circuits in synthetic biology.