title: Noise propagation in synthetic gene circuits for metabolic control.
abstract: Dynamic control of enzyme expression can be an effective strategy to engineer robust metabolic pathways. It allows a synthetic pathway to self-regulate in response to changes in bioreactor conditions or the metabolic state of the host. The implementation of this regulatory strategy requires gene circuits that couple metabolic signals with the genetic machinery, which is known to be noisy and one of the main sources of cell-to-cell variability. One of the unexplored design aspects of these circuits is the propagation of biochemical noise between enzyme expression and pathway activity. In this article, we quantify the impact of a synthetic feedback circuit on the noise in a metabolic product in order to propose design criteria to reduce cell-to-cell variability. We consider a stochastic model of a catalytic reaction under negative feedback from the product to enzyme expression. On the basis of stochastic simulations and analysis, we show that, depending on the repression strength and promoter strength, transcriptional repression of enzyme expression can amplify or attenuate the noise in the number of product molecules. We obtain analytic estimates for the metabolic noise as a function of the model parameters and show that noise amplification/attenuation is a structural property of the model. We derive an analytic condition on the parameters that lead to attenuation of metabolic noise, suggesting that a higher promoter sensitivity enlarges the parameter design space. In the theoretical case of a switch-like promoter, our analysis reveals that the ability of the circuit to attenuate noise is subject to a trade-off between the repression strength and promoter strength.
authors.affiliation: Department of Mathematics, ‡Centre for Synthetic Biology and Innovation, Department of Bioengineering, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Oyarzún
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Lugagne
authors.forename: Guy-Bart V
authors.initials: GB
authors.lastname: Stan
mesh_terms: D000465:Algorithms; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks / Q000235:genetics*; D060847:Metabolic Engineering; D008958:Models, Molecular; D011401:Promoter Regions, Genetic
chemical_list: D004798:Enzymes
keywords: biochemical noise; dynamic metabolic engineering; enzymatic reactions; feedback control design; genetic feedback circuits; promoter design