An Orthogonal Permease–Inducer–Repressor Feedback Loop Shows Bistability

Feedback loops in biological networks,
among others, enable differentiation
and cell cycle progression, and increase robustness in signal transduction.
In natural networks, feedback loops are often complex and intertwined,
making it challenging to identify which loops are mainly responsible
for an observed behavior. However, minimal synthetic replicas could
allow for such identification. Here, we engineered a synthetic permease-inducer-repressor
system in Saccharomyces cerevisiae to analyze if
a transport-mediated positive feedback loop could be a core mechanism
for the switch-like behavior in the regulation of metabolic gene networks
such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic
circuit using deterministic and stochastic mathematical models. Similar
to its natural counterparts, our synthetic system shows bistable and
hysteretic behavior, and the inducer concentration range for bistability
as well as the switching rates between the two stable states depend
on the repressor concentration. Our results indicate that a generic
permease–inducer–repressor circuit with a single feedback
loop is sufficient to explain the experimentally observed bistable
behavior of the natural systems. We anticipate that the approach of
reimplementing natural systems with orthogonal parts to identify crucial
network components is applicable to other natural systems such as
signaling pathways.