Building biological memory by linking positive feedback loops

A common topology found in many bistable genetic systems is two interacting positive feedback loops. Here we explore how this relatively simple topology can allow bistability over a large range of cellular conditions. On the basis of theoretical arguments, we predict that nonlinear interactions betw...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (1), p.175-180
Main Authors: Chang, Dong-Eun, Leung, Shelly, Atkinson, Mariette R, Reifler, Aaron, Forger, Daniel, Ninfa, Alexander J
Format: Article
Language:English
Subjects:
Biological Sciences
Cell cycle
Cells
Control loops
E coli
Escherichia coli
Escherichia coli - genetics
Escherichia coli Proteins - genetics
Experiments
Feedback, Physiological
Galactosides
Gene expression regulation
Gene Expression Regulation, Bacterial
Gene Regulatory Networks
Genes
Genes, Bacterial
Genetics
Kinetics
Membrane transport proteins
Models, Genetic
Operons
Periodicity
Positive feedback
Promoter Regions, Genetic
Recombinant Fusion Proteins - genetics
Repression
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Summary:A common topology found in many bistable genetic systems is two interacting positive feedback loops. Here we explore how this relatively simple topology can allow bistability over a large range of cellular conditions. On the basis of theoretical arguments, we predict that nonlinear interactions between two positive feedback loops can produce an ultrasensitive response that increases the range of cellular conditions at which bistability is observed. This prediction was experimentally tested by constructing a synthetic genetic circuit in Escherichia coli containing two well-characterized positive feedback loops, linked in a coherent fashion. The concerted action of both positive feedback loops resulted in bistable behavior over a broad range of inducer concentrations; when either of the feedback loops was removed, the range of inducer concentrations at which the system exhibited bistability was decreased by an order of magnitude. Furthermore, bistability of the system could be tuned by altering growth conditions that regulate the contribution of one of the feedback loops. Our theoretical and experimental work shows how linked positive feedback loops may produce the robust bistable responses required in cellular networks that regulate development, the cell cycle, and many other cellular responses.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0908314107