Coupled Mutual Inhibition and Mutual Activation Motifs as Tools for Cell-Fate Control

Multistability is central to biological systems. It plays a crucial role in adaptation, evolvability, and differentiation. The presence of positive feedback loops can enable multistability. 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 dynamical simulations across a large ensemble of parameter sets and initial conditions to study the bistability characteristics of these motifs. Furthermore, we investigate the utility of these motifs for achieving coordinated expression through cyclic and parallel coupling amongst them. Our analysis revealed that MI-based architectures offer discrete and robust control over gene expression, multistability, and coordinated expression among multiple genes, as compared to MA-based architectures. We then devised a combination of MI and MA architectures to improve coordination and multistability. Such designs help enhance our understanding of the control structures involved in robust cell-fate decisions and provide a way to achieve controlled decision-making in synthetic systems.