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Cotranscriptionally encoded RNA strand displacement circuits.

ABSTRACT: Engineered molecular circuits that process information in biological systems could address emerging human health and biomanufacturing needs. However, such circuits can be difficult to rationally design and scale. DNA-based strand displacement reactions have demonstrated the largest and most computationally powerful molecular circuits to date but are limited in biological systems due to the difficulty in genetically encoding components. Here, we develop scalable cotranscriptionally encoded RNA strand displacement (ctRSD) circuits that are rationally programmed via base pairing interactions. ctRSD circuits address the limitations of DNA-based strand displacement circuits by isothermally producing circuit components via transcription. We demonstrate circuit programmability in vitro by implementing logic and amplification elements, as well as multilayer cascades. Furthermore, we show that circuit kinetics are accurately predicted by a simple model of coupled transcription and strand displacement, enabling model-driven design. We envision ctRSD circuits will enable the rational design of powerful molecular circuits that operate in biological systems, including living cells.

SUBMITTER: Schaffter SW

PROVIDER: S-EPMC8942360 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Cotranscriptionally encoded RNA strand displacement circuits.

Schaffter Samuel W SW Strychalski Elizabeth A EA

Science advances 20220323 12

Engineered molecular circuits that process information in biological systems could address emerging human health and biomanufacturing needs. However, such circuits can be difficult to rationally design and scale. DNA-based strand displacement reactions have demonstrated the largest and most computationally powerful molecular circuits to date but are limited in biological systems due to the difficulty in genetically encoding components. Here, we develop scalable cotranscriptionally encoded RNA st ...[more]

PMID: 35319994

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Project description:BACKGROUND: The simplest conceivable example of evolving systems is RNA molecules that can replicate themselves. Since replication produces a new RNA strand complementary to a template, all templates would eventually become double-stranded and, hence, become unavailable for replication. Thus the problem of how to separate the two strands is considered a major issue for the early evolution of self-replicating RNA. One biologically plausible way to copy a double-stranded RNA is to displace a preexisting strand by a newly synthesized strand. Such copying can in principle be initiated from either the (+) or (-) strand of a double-stranded RNA. Assuming that only one of them, say (+), can act as replicase when single-stranded, strand displacement produces a new replicase if the (-) strand is the template. If, however, the (+) strand is the template, it produces a new template (but no replicase). Modern transcription exhibits extreme strand preference wherein anti-sense strands are always the template. Likewise, replication by strand displacement seems optimal if it also exhibits extreme strand preference wherein (-) strands are always the template, favoring replicase production. Here we investigate whether such strand preference can evolve in a simple RNA replicator system with strand displacement. RESULTS: We first studied a simple mathematical model of the replicator dynamics. Our results indicated that if the system is well-mixed, there is no selective force acting upon strand preference per se. Next, we studied an individual-based simulation model to investigate the evolution of strand preference under finite diffusion. Interestingly, the results showed that selective forces "emerge" because of finite diffusion. Strikingly, the direction of the strand preference that evolves [i.e. (+) or (-) strand excess] is a complex non-monotonic function of the diffusion intensity. The mechanism underlying this behavior is elucidated. Furthermore, a speciation-like phenomenon is observed under certain conditions: two extreme replication strategies, namely replicase producers and template producers, emerge and coexist among competing replicators. CONCLUSION: Finite diffusion enables the evolution of strand preference, the direction of which is a non-monotonic function of the diffusion intensity. By identifying the conditions under which strand preference evolves, this study provides an insight into how a rudimentary transcription-like pattern might have emerged in an RNA-based replicator system. REVIEWERS: This article was reviewed by Eugene V Koonin, Rob Kinght and István Scheuring (nominated by David H Ardell). For the full reviews, please go to the Reviewers' comments section.

Dataset Information

Cotranscriptionally encoded RNA strand displacement circuits.

Publications

Cotranscriptionally encoded RNA strand displacement circuits.

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