Robustness in spatially driven bistability in signaling systems

Abstract

Biological systems are spatially organized. This microscopic heterogeneity has been shown to produce emergent complex behaviors such as bistability. Even though the connection between spatiality and dynamic response is essential to understand biological output, its robustness and extent has not been sufficiently explored. This work focuses on a previously described system which is composed of two monostable modules acting on different cellular compartments and sharing species through linear shuttling reactions. One of the two main purposes of this paper is to quantify the frequency of occurrence of bistability throughout the parameter space and to identify which parameters and in which value ranges control the emergence and the properties of bistability. We found that a very small fraction of the sampled parameter space produced a bistable response. Most importantly, shuttling parameters were among the most influential ones to control this property. The other goal of this paper is to simplify the same system as much as possible without losing compartment-induced bistability. This procedure provided a simplified model that still connects two monostable systems by a reduced set of linear shuttling reactions that circulates all the species around the two compartments. Bistable systems are one of the main building blocks of more complex behaviors such as oscillations, memory, and digitalization. Therefore, we expect that the proposed minimal system provides insight into how these behaviors can arise from compartmentalization.

A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems

“…Furthermore, our results can be used to analyze other types of bistable modules, since it works on very different cases like the DP cycle and an auto-catalytic node, plus a double positive interaction case 50 . A simple phosphorylation cycle with translocation between compartments has been studied for its bistability 51 , and adding sequestration could result in oscillations (like it occurs for the DP cycle). And a 2018 work by Perez-Carrasco et al shows the behavior that arises from combining a toggle switch and a repressilator, that is not found when both modules are separated 52 .…”

Algebraic Geometry Tools in Systems Biology

“…This "coupling" of biological systems, spatially organized, can produce emergent complex behavior, in particular, multistationarity. Several mathematical [18] to analyze these models and identify minimal subnetworks which are bistable, but these tools also require an intensive parameter sampling and simulation.…”