Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters

Multistable switches are ubiquitous building blocks in both systems and synthetic biology. Given their central role, it is thus imperative to understand how their fundamental properties depend not only on the tunable biophysical properties of the switches themselves, but also on their genetic contex...

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Autor principal:	Andras Gyorgy
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	genetic switch leaky promoter multistability robustness context-dependence scarce resources Science Q
Acceso en línea:	https://doaj.org/article/96eafc2355134b4daf9441991f1d438f
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spelling	oai:doaj.org-article:96eafc2355134b4daf9441991f1d438f2021-11-25T18:10:42ZContext-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters10.3390/life111111502075-1729https://doaj.org/article/96eafc2355134b4daf9441991f1d438f2021-10-01T00:00:00Zhttps://www.mdpi.com/2075-1729/11/11/1150https://doaj.org/toc/2075-1729Multistable switches are ubiquitous building blocks in both systems and synthetic biology. Given their central role, it is thus imperative to understand how their fundamental properties depend not only on the tunable biophysical properties of the switches themselves, but also on their genetic context. To this end, we reveal in this article how these factors shape the essential characteristics of toggle switches implemented using leaky promoters such as their stability and robustness to noise, both at single-cell and population levels. In particular, our results expose the roles that competition for scarce transcriptional and translational resources, promoter leakiness, and cell-to-cell heterogeneity collectively play. For instance, the interplay between protein expression from leaky promoters and the associated cost of relying on shared cellular resources can give rise to tristable dynamics even in the absence of positive feedback. Similarly, we demonstrate that while promoter leakiness always acts against multistability, resource competition can be leveraged to counteract this undesirable phenomenon. Underpinned by a mechanistic model, our results thus enable the context-aware rational design of multistable genetic switches that are directly translatable to experimental considerations, and can be further leveraged during the synthesis of large-scale genetic systems using computer-aided biodesign automation platforms.Andras GyorgyMDPI AGarticlegenetic switchleaky promotermultistabilityrobustnesscontext-dependencescarce resourcesScienceQENLife, Vol 11, Iss 1150, p 1150 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	genetic switch leaky promoter multistability robustness context-dependence scarce resources Science Q
spellingShingle	genetic switch leaky promoter multistability robustness context-dependence scarce resources Science Q Andras Gyorgy Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
description	Multistable switches are ubiquitous building blocks in both systems and synthetic biology. Given their central role, it is thus imperative to understand how their fundamental properties depend not only on the tunable biophysical properties of the switches themselves, but also on their genetic context. To this end, we reveal in this article how these factors shape the essential characteristics of toggle switches implemented using leaky promoters such as their stability and robustness to noise, both at single-cell and population levels. In particular, our results expose the roles that competition for scarce transcriptional and translational resources, promoter leakiness, and cell-to-cell heterogeneity collectively play. For instance, the interplay between protein expression from leaky promoters and the associated cost of relying on shared cellular resources can give rise to tristable dynamics even in the absence of positive feedback. Similarly, we demonstrate that while promoter leakiness always acts against multistability, resource competition can be leveraged to counteract this undesirable phenomenon. Underpinned by a mechanistic model, our results thus enable the context-aware rational design of multistable genetic switches that are directly translatable to experimental considerations, and can be further leveraged during the synthesis of large-scale genetic systems using computer-aided biodesign automation platforms.
format	article
author	Andras Gyorgy
author_facet	Andras Gyorgy
author_sort	Andras Gyorgy
title	Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
title_short	Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
title_full	Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
title_fullStr	Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
title_full_unstemmed	Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
title_sort	context-dependent stability and robustness of genetic toggle switches with leaky promoters
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/96eafc2355134b4daf9441991f1d438f
work_keys_str_mv	AT andrasgyorgy contextdependentstabilityandrobustnessofgenetictoggleswitcheswithleakypromoters
_version_	1718411511882317824

Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters

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