Theoretical investigation of a genetic switch for metabolic adaptation.

Kathrin S Laxhuber,Rob Phillips,Griffin Chure,Charlotte Strandkvist,Kyle L Naughton,Muir J Morrison,Nathan M Belliveau

doi:10.1371/journal.pone.0226453

Abstract

Membrane transporters carry key metabolites across the cell membrane and, from a resource standpoint, are hypothesized to be produced when necessary. The expression of membrane transporters in metabolic pathways is often upregulated by the transporter substrate. In E. coli, such systems include for example the lacY, araFGH, and xylFGH genes, which encode for lactose, arabinose, and xylose transporters, respectively. As a case study of a minimal system, we build a generalizable physical model of the xapABR genetic circuit, which features a regulatory feedback loop via membrane transport (positive feedback) and enzymatic degradation (negative feedback) of an inducer. Dynamical systems analysis and stochastic simulations show that the membrane transport makes the model system bistable in certain parameter regimes. Thus, it serves as a genetic "on-off" switch, enabling the cell to only produce a set of metabolic enzymes when the corresponding metabolite is present in large amounts. We find that the negative feedback from the degradation enzyme does not significantly disturb the positive feedback from the membrane transporter. We investigate hysteresis in the switching and discuss the role of cooperativity and multiple binding sites in the model circuit. Fundamentally, this work explores how a stable genetic switch for a set of enzymes is obtained from transcriptional auto-activation of a membrane transporter through its substrate.

Highlights

Genetic regulatory circuits are fundamental building blocks of functioning cells and organisms
The key feature of the type of system we investigate is the indirect activation of the transporter gene by the transporter substrate, leading to positive feedback similar to the aforementioned “on-off” switch
We focus on the xapABR genetic circuit from E. coli as a case study

Summary

Introduction

Genetic regulatory circuits are fundamental building blocks of functioning cells and organisms. One abundant class of these circuits are genetic switches. Their construction and function may differ, their common feature is bistability: their output gene expression will flow to and remain at one of two steady-state levels. The distribution of gene expression in a cell culture can be bimodal. This is not to be confused with mere stochastic bimodality, where the system is not stable, and the gene expression in each cell can fluctuate between the two levels.

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