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Engineering modular 'ON' RNA switches using biological components.

ABSTRACT: Riboswitches are cis-acting regulatory elements broadly distributed in bacterial mRNAs that control a wide range of critical metabolic activities. Expression is governed by two distinct domains within the mRNA leader: a sensory 'aptamer domain' and a regulatory 'expression platform'. Riboswitches have also received considerable attention as important tools in synthetic biology because of their conceptually simple structure and the ability to obtain aptamers that bind almost any conceivable small molecule using in vitro selection (referred to as SELEX). In the design of artificial riboswitches, a significant hurdle has been to couple the two domains enabling their efficient communication. We previously demonstrated that biological transcriptional 'OFF' expression platforms are easily coupled to diverse aptamers, both biological and SELEX-derived, using simple design rules. Here, we present two modular transcriptional 'ON' riboswitch expression platforms that are also capable of hosting foreign aptamers. We demonstrate that these biological parts can be used to facilely generate artificial chimeric riboswitches capable of robustly regulating transcription both in vitro and in vivo. We expect that these modular expression platforms will be of great utility for various synthetic biological applications that use RNA-based biosensors.

SUBMITTER: Ceres P

PROVIDER: S-EPMC3905868 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Engineering modular 'ON' RNA switches using biological components.

Ceres Pablo P Trausch Jeremiah J JJ Batey Robert T RT

Nucleic acids research 20130902 22

Riboswitches are cis-acting regulatory elements broadly distributed in bacterial mRNAs that control a wide range of critical metabolic activities. Expression is governed by two distinct domains within the mRNA leader: a sensory 'aptamer domain' and a regulatory 'expression platform'. Riboswitches have also received considerable attention as important tools in synthetic biology because of their conceptually simple structure and the ability to obtain aptamers that bind almost any conceivable small ...[more]

PMID: 23999097

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Project description:BACKGROUND:Bistability and ability to switch between two stable states is the hallmark of cellular responses. Cellular signaling pathways often contain bistable switches that regulate the transmission of the extracellular information to the nucleus where important biological functions are executed. RESULTS:In this work we show how the method of Gröebner bases can be used to detect bistability and output switchability. The method of Gröebner bases can be seen as a multivariate, non-linear generalization of the Gaussian elimination for linear systems which conveniently seperates the variables and drastically simplifies the simultaneous solution of polynomial equations. A necessary condition for fixed-point state bistability is for the Gröbner basis to have three distinct solutions for the state. A sufficient condition is provided by the eigenvalues of the local Jacobians. We also introduce the concept of output switchability which is defined as the ability of an output of a bistable system to switch between two different stable steady-state values. It is shown that bistability does not necessarily guarantee switchability of every state variable of the system. We further show that, for a bistable system, the necessary conditions for output switchability can be derived using the Gröebner basis. The theoretical results are incorporated into an analysis procedure and applied to several systems including the AKT (Protein kinase B), RAS (Rat Sarcoma) and MAPK (Mitogen-activated protein kinase) signal transduction pathways. Results demonstrate that the Gröebner bases can be conveniently used to analyze biological switches by simultaneously detecting bistability and output switchability. CONCLUSION:The Gröebner bases provides a novel methodology to analyze bistability. Results clarify the distinction between bistability and output switchability which is lacking in the literature. We have shown that theoretically, it is possible to have an output subspace of an n-dimensional bistable system where certain variables cannot switch. It is possible to construct such systems as we have done with two reaction networks.

Dataset Information

Engineering modular 'ON' RNA switches using biological components.

Publications

Engineering modular 'ON' RNA switches using biological components.

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