Queueing up for enzymatic processing: correlated signaling through coupled degradation

Cookson, Natalie A.; Mather, William; Danino, Tal; Mondragón-Palomino, Octavio; Williams, Ruth; Tsimring, Lev S.; Hasty, Jeff

doi:10.1038/msb.2011.94

Cited by 176 publications

(228 citation statements)

References 42 publications

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“…Note that the enzymatic decay of each protein depends on the concentration of both, because both AraC and LacI are targeted by the same protease (39). All parameter values are provided in the Table S1.…”

Section: Resultsmentioning

confidence: 99%

Engineered temperature compensation in a synthetic genetic clock

Hussain

Gupta

Hirning

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic biology promises to revolutionize biotechnology by providing the means to reengineer and reprogram cellular regulatory mechanisms. However, synthetic gene circuits are often unreliable, as changes to environmental conditions can fundamentally alter a circuit's behavior. One way to improve robustness is to use intrinsic properties of transcription factors within the circuit to buffer against intra-and extracellular variability. Here, we describe the design and construction of a synthetic gene oscillator in Escherichia coli that maintains a constant period over a range of temperatures. We started with a previously described synthetic dual-feedback oscillator with a temperature-dependent period. Computational modeling predicted and subsequent experiments confirmed that a single amino acid mutation to the core transcriptional repressor of the circuit results in temperature compensation. Specifically, we used a temperature-sensitive lactose repressor mutant that loses the ability to repress its target promoter at high temperatures. In the oscillator, this thermoinduction of the repressor leads to an increase in period at high temperatures that compensates for the decrease in period due to Arrhenius scaling of the reaction rates. The result is a transcriptional oscillator with a nearly constant period of 48 min for temperatures ranging from 30°C to 41°C. In contrast, in the absence of the mutation the period of the oscillator drops from 60 to 30 min over the same temperature range. This work demonstrates that synthetic gene circuits can be engineered to be robust to extracellular conditions through protein-level modifications.LacI | circadian oscillator | microfluidics | cellular dynamics | delay

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Section: Resultsmentioning

confidence: 99%

Engineered temperature compensation in a synthetic genetic clock

Hussain

Gupta

Hirning

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…12 could be replicated by an enzymatic degradation in a saturated regime (see ref. 28 for a biological instance of such a mechanism). In summary, the proposed chemical equivalent to Eq.…”

Section: Biochemical Network To Implement the Ratio Test For Concentmentioning

confidence: 99%

Decisions on the fly in cellular sensory systems

Siggia

Vergassola

2013

Proc. Natl. Acad. Sci. U.S.A.

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Cells send and receive signals through pathways that have been defined in great detail biochemically, and it is often presumed that the signals convey only level information. Cell signaling in the presence of noise is extensively studied but only rarely is the speed required to make a decision considered. However, in the immune system, rapidly developing embryos, and cellular response to stress, fast and accurate actions are required. Statistical theory under the rubric of "exploit-explore" quantifies trade-offs between decision speed and accuracy and supplies rigorous performance bounds and algorithms that realize them. We show that common protein phosphorylation networks can implement optimal decision theory algorithms and speculate that the ubiquitous chemical modifications to receptors during signaling actually perform analog computations. We quantify performance trade-offs when the cellular system has incomplete knowledge of the data model. For the problem of sensing the time when the composition of a ligand mixture changes, we find a nonanalytic dependence on relative concentrations and specify the number of parameters needed for near-optimal performance and how to adjust them. The algorithms specify the minimal computation that has to take place on a single receptor before the information is pooled across the cell.signal transduction | sequential probability ratio test T he exigencies of operations research during the second world war led to the following problem: Given a stream of data that is drawn from one of two prescribed models M1 or M2, what is the quickest way to decide between them subject to bounds on the errors? The solution found by Wald (1, 2) computes the ratio of two conditional probabilities using the data up to time t, RðtÞ ¼ Pðdataj M1Þ=Pðdataj M2Þ;[1]and calls M1 when R > H1 and M2 when R < H2 and waits for more data otherwise. The thresholds H control the errors; e.g., larger H1 decreases the odds of deciding M1 when the data come from M2. For the task of distinguishing two Gaussians with different means, the average decision time for Wald's algorithm is a factor two times shorter than using a fixed averaging time for the same error rate. This is a simple example of a general class of problems termed "exploit-explore"; i.e., either decide or accumulate more data (3, 4). They are used in medical statistics to decide when a clinical trial has generated enough data for a conclusion. For the problems that concern us, the next step in complexity was taken by Shiryaev (5-7), who considered the optimal detection of change points. A stream of data is presented and the model changes from M1 to M2 at an unknown time θ. The algorithm calls the change point at time t to minimize a linear combination of the false positive rate (e.g., t ≤ θ) and the decision time mean ðt − θÞ when t > θ. Again the algorithm "knows" the models M1, M2.Another step in complexity, about which we have little to say, corresponds to situations where the statistics of the hypotheses to be discriminated are not available or ...

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“…Further computational studies have found that, because modules share limited amounts of transcriptional/translational resources, the expression levels of proteins in seemingly unconnected modules become surprisingly coupled [55,56] and the dynamical behavior of simple activation cascades becomes unpredictable [57]. Counter-intuitive interactions have also been experimentally observed when di↵erent modules share common enzymes, whose scarcity leads to interesting synchronized behavior [58]. All these e↵ects make a module's salient properties poorly predictable and, as a result, confound system design.…”

Section: Modularity Of Functional Modules: the E↵ects Of Resource Shamentioning

confidence: 99%

Modularity, context-dependence, and insulation in engineered biological circuits

Vecchio¹

2015

Trends in Biotechnology

121

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Abstract. The ability of linking systems together such that they behave as predicted once interacting with each other is an essential requirement for the forward engineering of robust synthetic biological circuits. Unfortunately, because of context dependencies, parts and functional modules often behave unpredictably once interacting in the cellular environment. In this paper, we review some recent advances toward establishing a rigorous engineering framework for insulating parts and modules from their context to improve modularity. Overall, a synergy between engineering better parts and higher-level circuit design that overcome the physical limitations of available parts will be important to resolve the problem of context dependence. Modularity and context-dependence in engineered biological systemsSynthetic biology, that is, the use of molecular biology techniques to forward engineer cellular behavior, is a rising branch of biological research [1]. One aim of the field is to gather a better understanding of natural systems by re-wiring their subsystems and exporting them to new settings. The ability of re-designing living systems has especially potential in the biotechnology industry, promising a number of breakthroughs in human health and the environment. Designing living systems does not simply relay on the engineering of parts, such as proteins or genetic sequences. In contrast, it essentially requires the ability of linking parts together to create sophisticated functionalities. Linking parts together to achieve a predictable behavior is 1

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Queueing up for enzymatic processing: correlated signaling through coupled degradation

Abstract: Overloaded enzymatic processes are shown to create indirect coupling between upstream components in cellular networks. This has important implications for the design of synthetic biology devices and for our understanding of currently inexplicable links within endogenous biological systems.

Cited by 176 publications

References 42 publications

Engineered temperature compensation in a synthetic genetic clock

Engineered temperature compensation in a synthetic genetic clock

Decisions on the fly in cellular sensory systems

Modularity, context-dependence, and insulation in engineered biological circuits

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