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Autoinhibited transient, gated, and cascaded dynamic transcription of RNAs.

ABSTRACT: Following transient spatiotemporal misregulation of gene expression programs by native transcription machineries, we introduce a versatile biomimetic concept to design transient dynamic transcription machineries, revealing gated and cascaded temporal transcription of RNAs. The concept is based on the engineering of the reaction module consisting of malachite green (MG) and/or DFHBI {(5Z)-5-[(3,5-difluoro-4-hydroxyphenyl)methylene]-3,5-dihydro-2,3-dimethyl-4H-imidazol-4-one} DNA scaffolds, T7 RNA polymerase (RNAP) aptamer transcription scaffold, and the inhibited T7 RNAP-aptamer complex. In the presence of the counter RNAP aptamer strand and ribonucleoside triphosphates, the triggered activation of the three transcription scaffolds are activated, leading to the transcription of the MG and/or DFHBI RNA aptamer and to the transcription of the RNAP aptamer acting as an autoinhibitor that leads to the transient temporal, dissipative, and blockage of all transcription. By appropriate design of the transcription scaffolds and the inhibitors/coupler, transient gated and cascaded transcription processes are demonstrated, and a bimodal transcription module synthesizing a transient operating ribozyme is introduced.

SUBMITTER: Li Z

PROVIDER: S-EPMC9385147 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Autoinhibited transient, gated, and cascaded dynamic transcription of RNAs.

Li Zhenzhen Z Wang Jianbang J Willner Itamar I

Science advances 20220817 33

Following transient spatiotemporal misregulation of gene expression programs by native transcription machineries, we introduce a versatile biomimetic concept to design transient dynamic transcription machineries, revealing gated and cascaded temporal transcription of RNAs. The concept is based on the engineering of the reaction module consisting of malachite green (MG) and/or DFHBI {(5Z)-5-[(3,5-difluoro-4-hydroxyphenyl)methylene]-3,5-dihydro-2,3-dimethyl-4<i>H</i>-imidazol-4-one} DNA scaffolds, ...[more]

PMID: 35977022

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Project description:Large, naturally evolved biomolecular networks typically fulfil multiple functions. When modelling or redesigning such systems, functional subsystems are often analysed independently first, before subsequent integration into larger-scale computational models. In the design and analysis process, it is therefore important to quantitatively analyse and predict the dynamics of the interactions between integrated subsystems; in particular, how the incremental effect of integrating a subsystem into a network depends on the existing dynamics of that network. In this paper we present a framework for simulating the contribution of any given functional subsystem when integrated together with one or more other subsystems. This is achieved through a cascaded layering of a network into functional subsystems, where each layer is defined by an appropriate subset of the reactions. We exploit symmetries in our formulation to exhaustively quantify each subsystem's incremental effects with minimal computational effort. When combining subsystems, their isolated behaviour may be amplified, attenuated, or be subject to more complicated effects. We propose the concept of mutual dynamics to quantify such nonlinear phenomena, thereby defining the incompatibility and cooperativity between all pairs of subsystems when integrated into any larger network. We exemplify our theoretical framework by analysing diverse behaviours in three dynamic models of signalling and metabolic pathways: the effect of crosstalk mechanisms on the dynamics of parallel signal transduction pathways; reciprocal side-effects between several integral feedback mechanisms and the subsystems they stabilise; and consequences of nonlinear interactions between elementary flux modes in glycolysis for metabolic engineering strategies. Our analysis shows that it is not sufficient to just specify subsystems and analyse their pairwise interactions; the environment in which the interaction takes place must also be explicitly defined. Our framework provides a natural representation of nonlinear interaction phenomena, and will therefore be an important tool for modelling large-scale evolved or synthetic biomolecular networks.

Dataset Information

Autoinhibited transient, gated, and cascaded dynamic transcription of RNAs.

Publications

Autoinhibited transient, gated, and cascaded dynamic transcription of RNAs.

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