Emergent Bistable Switches from the Incoherent Feed-Forward Signaling of a Positive Feedback Loop

Bistability is intrinsically connected to various decision making processes in living systems. The operating principles of a bistable switch, generated from a positive feedback loop, are well understood both in natural and synthetic settings. However, the fate of dynamic modularity of a positive feedback loop is unknown when it is connected to another dynamically modular signaling motif. In order to address this, here we investigate feed-forward signaling of a positive feedback loop to determine the fate of a bistable switch under such signaling. Using the potential energy based high-throughput bifurcation analysis method, we uncover that in addition to the conventional bistability the hybrid motifs generate various emergent bistable switches, namely mushroom and isola switches, which are not produced by the individual motifs. Using random parameter sampling, network perturbation, and phase plane analysis, we establish the design principles of such emergent behaviors. Incoherent feed-forward signaling of a positive feedback loop with distinct regulatory thresholds of the two arms of the feed-forward loop are the key requirements for such emergent behaviors. Our calculations show that the specific types of atypical bistable responses depend on the logic gate configuration of the signals. However, the emergent bistable behaviors of the hybrid networks do not depend on the nature of the positive feedback loop.