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Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability
BACKGROUND: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable,...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895904/ https://www.ncbi.nlm.nih.gov/pubmed/27266276 http://dx.doi.org/10.1186/s12918-016-0279-y |
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author | Martyushenko, Nikolay Johansen, Sigurd Hagen Ghim, Cheol-Min Almaas, Eivind |
author_facet | Martyushenko, Nikolay Johansen, Sigurd Hagen Ghim, Cheol-Min Almaas, Eivind |
author_sort | Martyushenko, Nikolay |
collection | PubMed |
description | BACKGROUND: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable, or even to multistable, based on the experimental fine-tuning of readily accessible parameters. In order to successfully design robust, bistable synthetic circuits to be used as biomolecular probes, or understand modes of operation of such naturally occurring circuits, we must identify parameters that are key in determining their characteristics. RESULTS: Here, we analyze the bistability properties of a general, asymmetric genetic toggle switch based on a chemical-reaction kinetic description. By making appropriate approximations, we are able to reduce the system to two coupled differential equations. Their deterministic stability analysis and stochastic numerical simulations are in excellent agreement. Drawing upon this general framework, we develop a model of an experimentally realized asymmetric bistable genetic switch based on the LacI and TetR repressors. By varying the concentrations of two synthetic inducers, doxycycline and isopropyl β-D-1-thiogalactopyranoside, we predict that it will be possible to repeatedly fine-tune the mode of operation of this genetic switch from monostable to bistable, as well as the switching rates over many orders of magnitude, in an experimental setting. Furthermore, we find that the shape and size of the bistability region is closely connected with plasmid copy number. CONCLUSIONS: Based on our numerical calculations of the LacI-TetR asymmetric bistable switch phase diagram, we propose a generic work-flow for developing and applying biomolecular probes: Their initial state of operation should be specified by controlling inducer concentrations, and dilution due to cellular division would turn the probes into memory devices in which information could be preserved over multiple generations. Additionally, insights from our analysis of the LacI-TetR system suggest that this particular system is readily available to be employed in this kind of probe. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0279-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4895904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48959042016-06-08 Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability Martyushenko, Nikolay Johansen, Sigurd Hagen Ghim, Cheol-Min Almaas, Eivind BMC Syst Biol Research Article BACKGROUND: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable, or even to multistable, based on the experimental fine-tuning of readily accessible parameters. In order to successfully design robust, bistable synthetic circuits to be used as biomolecular probes, or understand modes of operation of such naturally occurring circuits, we must identify parameters that are key in determining their characteristics. RESULTS: Here, we analyze the bistability properties of a general, asymmetric genetic toggle switch based on a chemical-reaction kinetic description. By making appropriate approximations, we are able to reduce the system to two coupled differential equations. Their deterministic stability analysis and stochastic numerical simulations are in excellent agreement. Drawing upon this general framework, we develop a model of an experimentally realized asymmetric bistable genetic switch based on the LacI and TetR repressors. By varying the concentrations of two synthetic inducers, doxycycline and isopropyl β-D-1-thiogalactopyranoside, we predict that it will be possible to repeatedly fine-tune the mode of operation of this genetic switch from monostable to bistable, as well as the switching rates over many orders of magnitude, in an experimental setting. Furthermore, we find that the shape and size of the bistability region is closely connected with plasmid copy number. CONCLUSIONS: Based on our numerical calculations of the LacI-TetR asymmetric bistable switch phase diagram, we propose a generic work-flow for developing and applying biomolecular probes: Their initial state of operation should be specified by controlling inducer concentrations, and dilution due to cellular division would turn the probes into memory devices in which information could be preserved over multiple generations. Additionally, insights from our analysis of the LacI-TetR system suggest that this particular system is readily available to be employed in this kind of probe. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0279-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-06-06 /pmc/articles/PMC4895904/ /pubmed/27266276 http://dx.doi.org/10.1186/s12918-016-0279-y Text en © Martyushenko et al. 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Martyushenko, Nikolay Johansen, Sigurd Hagen Ghim, Cheol-Min Almaas, Eivind Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title | Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title_full | Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title_fullStr | Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title_full_unstemmed | Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title_short | Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
title_sort | hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895904/ https://www.ncbi.nlm.nih.gov/pubmed/27266276 http://dx.doi.org/10.1186/s12918-016-0279-y |
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