Coupled mutual inhibition and mutual activation motifs as tools for cell-fate control

Abstract

Multistability is central to biological systems as it plays a key role in adaptation, evolvability, and differentiation. Multistability can be achieved by integrating positive feedback loops into the regulation. The simplest of such feedback loops are a) a mutual inhibition (MI) loop, b) a mutual activation (MA) loop, and, c) self-activation. While it is established that all three motifs can give rise to bistability, the characteristic differences in the bistability exhibited by each of these motifs is relatively less understood. Here, we use ODE-based simulations across a large ensemble of parameter sets and initial conditions to study the characteristics of the bistability of these motifs and their limits in the parameter space. We also examine the behavior of these motifs under mutual degradation and self-activation. Finally, we investigate the utility of these motifs for achieving coordinated expression through cyclic and parallel coupling. Through our analysis, we found that MI-based architectures offer robustness in maintaining distinct multistability and allow for coordination among multiple genes. This coordination paves way for understanding the naturally occurring gene regulatory network and may also help in the better design of robust and controllable synthetic networks.