title: An Orthogonal Permease-Inducer-Repressor Feedback Loop Shows Bistability.
abstract: 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.
authors.affiliation: Life Science Zurich Ph.D. Program on Molecular and Translational Biomedicine, and Competence Centre for Personalized Medicine, ETH Zurich , 8093 Zurich, Switzerland.|D-BSSE, ETH Zurich and Swiss Institute of Bioinformatics , Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Gnügge
authors.affiliation: D-BSSE, ETH Zurich and Swiss Institute of Bioinformatics , Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Lekshmi
authors.initials: L
authors.lastname: Dharmarajan
authors.affiliation: D-BSSE, ETH Zurich and Swiss Institute of Bioinformatics , Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Moritz
authors.initials: M
authors.lastname: Lang
authors.affiliation: D-BSSE, ETH Zurich and Swiss Institute of Bioinformatics , Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stelling
mesh_terms: D003001:Cloning, Molecular; D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D005818:Genetic Engineering; D007763:Lac Operon; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000074041:Microorganisms, Genetically-Modified; D008962:Models, Theoretical; D010957:Plasmids / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins
keywords: S. cerevisiae; bistability; genetic circuit; hysteresis; switch; synthetic biology