Dynamically Reshaping Signaling Networks to Program Cell Fate via Genetic Controllers

Galloway, Kate E.; Franco, Elisa; Smolke, Christina D.

doi:10.1126/science.1235005

Cited by 67 publications

(64 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has allowed the rational engineering of parts and genetic circuits useful for a range of applications in biotechnology. Although most of the genetic devices originate from prokaryotes, transplantation into eukaryotes has been reported for bioswitches, used to construct orthogonal genetic devices to control a cellular response to a defined input 14,44,45 . Specifically, genetic devices enabling the manipulation of transcription through the transplantation of prokaryote transcriptional repressors have inspired researchers, in their quest for tools to screen, select and actuate cellular responses 17,46 .…”

Section: Discussionmentioning

confidence: 99%

Engineering prokaryotic transcriptional activators as metabolite biosensors in yeast

et al. 2016

View full text Add to dashboard Cite

TitleEngineering prokaryotic transcriptional activators as metabolite biosensors in yeast io-based production of chemicals and fuels is an attractive avenue to reduce dependence on petroleum. For bio-based production, biocatalysts must often be genetically modified to increase production. However, the current efficiency of genomeengineering methods and parts prospecting allows for unprecedented genotype diversity that vastly outstrips our ability to screen for best cell performance 1,2 .To meet current demand, bioengineers have started to develop genetically encoded devices and systems that enable screening and selection of better-performing biocatalysts in higher throughput. Genetic devices including oscillators, amplifiers and recorders, which have been developed based on fine-tuned relationships between input and output signals, are promising tools for programming and controlling gene expression in living cells [3][4][5] . These devices sense extracellular or intracellular perturbations and actuate cellular decision-making processes akin to logic gates in electrical circuits. Hence, from a diverse set of inputs, molecular gating components such as RNA aptamers and allosterically regulated transcription factors have been engineered to control outputs for applications such as high-throughput screening, actuation on cellular metabolism and evolution-based selection of optimal cell performance [6][7][8] .A key component in many of the reported devices is a ligandinducible transcriptional regulator. Transcriptional regulators are straightforward and powerful components, with many uses in genetic designs. Owing to their modular structure, transcriptional regulators have proven to be versatile platforms for genetically encoded Boolean logic functions 9,10 . In particular, gene switches based on ligand-binding transcriptional repressors bind to genomic targets in the absence of their cognate ligand and thereby repress gene expression of the downstream gene(s), whereas binding between ligand and repressor causes the release of the repressor from the DNA and thereby a derepression 11 . In such 'NOT' gates, simple steric hindrance of RNA polymerase progression, as in the case of the tetracycline-responsive gene switch TetR, have for decades been used for conditional control of gene expression in both prokaryotic and eukaryotic chassis 12,13 . Transcriptional repressors and other artificial transcriptional regulators can be further engineered, for example, via the addition of nuclear localization signals, destabilization domains and transcriptional activation regions, to repurpose conditional repressors into activators [13][14][15] . Though conceptually intriguing and practically relevant, the repurposing of logic gates can suffer from the inherent need for extensive engineering 9,16,17 .Though most ligand-inducible genetic devices adopted for eukaryotes historically have been founded on transcriptional repressors, a hitherto untapped resource for use in genetic designs is ligand-inducible transcriptional activators. Bac...

show abstract

Section: Discussionmentioning

confidence: 99%

Engineering prokaryotic transcriptional activators as metabolite biosensors in yeast

et al. 2016

View full text Add to dashboard Cite

show abstract

“…First, RNA circuitry has the potential to be compact (RNA regulators are typically 10-100s nucleotides long) which permits rapid construction [31 ], reduces cellular burden, and aids efficient delivery of circuits into mammalian cells [33]. Second, RNA regulators have been shown to be highly composable, which simplifies the design of RNA-only circuits [14 ,17 ,18] and allows easier integration with proteins to create protein-RNA hybrid circuits [34]. Finally, RNA circuits have the potential to propagate signals much faster than protein circuits, since signal propagation speed is determined by the fast degradation rates of RNAs.…”

Section: Rna-based Genetic Circuitsmentioning

confidence: 99%

A renaissance in RNA synthetic biology: new mechanisms, applications and tools for the future

Chappell

Watters

Takahashi

et al. 2015

Current Opinion in Chemical Biology

146

132

View full text Add to dashboard Cite

Since our ability to engineer biological systems is directly related to our ability to control gene expression, a central focus of synthetic biology has been to develop programmable genetic regulatory systems. Researchers are increasingly turning to RNA regulators for this task because of their versatility, and the emergence of new powerful RNA design principles. Here we review advances that are transforming the way we use RNAs to engineer biological systems. First, we examine new designable RNA mechanisms that are enabling large libraries of regulators with protein-like dynamic ranges. Next, we review emerging applications, from RNA genetic circuits to molecular diagnostics. Finally, we describe new experimental and computational tools that promise to accelerate our understanding of RNA folding, function and design.

show abstract

“…So far, several synthetic devices have been designed and implemented in vivo using protein expression and gene regulation mechanisms: for example, logic gates [1], memory elements [2], oscillators [3], filters [4]- [5] and controllers of cellular differential processes [6]. However, the problem of imparting a programmable robust dynamic behaviour to such synthetic biological circuits has remained open, primarily because a proper understanding of the input-output properties of genetic components is still currently lacking, especially in the context of their interactions with the host cell within which these circuits operate.…”

Section: Introductionmentioning

confidence: 99%

Biomolecular implementation of nonlinear system theoretic operators

Foo

Sawlekar

Kim³

et al. 2016

2016 European Control Conference (ECC)

View full text Add to dashboard Cite

Abstract-Synthesis of biomolecular circuits for controlling molecular-scale processes is an important goal of synthetic biology with a wide range of in vitro and in vivo applications, including biomass maximization, nanoscale drug delivery, and many others. In this paper, we present new results on how abstract chemical reactions can be used to implement commonly used system theoretic operators such as the polynomial functions, rational functions and Hill-type nonlinearity. We first describe how idealised versions of multi-molecular reactions, catalysis, annihilation, and degradation can be combined to implement these operators. We then show how such chemical reactions can be implemented using enzyme-free, entropydriven DNA reactions. Our results are illustrated through three applications: (1) implementation of a Stan-Sepulchre oscillator, (2) the computation of the ratio of two signals, and (3) a PI+antiwindup controller for regulating the output of a static nonlinear plant.

show abstract

Dynamically Reshaping Signaling Networks to Program Cell Fate via Genetic Controllers

Cited by 67 publications

References 57 publications

Engineering prokaryotic transcriptional activators as metabolite biosensors in yeast

Engineering prokaryotic transcriptional activators as metabolite biosensors in yeast

A renaissance in RNA synthetic biology: new mechanisms, applications and tools for the future

Biomolecular implementation of nonlinear system theoretic operators

Contact Info

Product

Resources

About