Effects of cell cycle noise on excitable gene circuits

Veliz-Cuba, Alan; Gupta, Chinmaya; Bennett, Matthew R.; Josić, Krešimir; Ott, William

doi:10.1088/1478-3975/13/6/066007

Cited by 5 publications

(5 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such systems have been studied both experimentally and theoretically, as well as by means of synthetic biology [ 12 , 13 ]. In theoretical studies, cell divisions were either accounted implicitly (by protein dilutions) [ 12 – 14 ], or it was assumed that interacting genes replicate at the same time point of the cycle [ 6 , 15 – 18 ]. Also in synthetic biology research the competing genes were introduced on the same plasmid [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic toggle switch controlled by bacterial growth rate

Jaruszewicz-Błońska

Lipniacki

2017

BMC Syst Biol

View full text Add to dashboard Cite

BackgroundIn favorable conditions bacterial doubling time is less than 20 min, shorter than DNA replication time. In E. coli a single round of genome replication lasts about 40 min and it must be accomplished about 20 min before cell division. To achieve such fast growth rates bacteria perform multiple replication rounds simultaneously. As a result, when the division time is as short as 20 min E. coli has about 8 copies of origin of replication (ori) and the average copy number of the genes situated close to ori can be 4 times larger than those near the terminus of replication (ter). It implies that shortening of cell cycle may influence dynamics of regulatory pathways involving genes placed at distant loci.ResultsWe analyze this effect in a model of a genetic toggle switch, i.e. a system of two mutually repressing genes, one localized in the vicinity of ori and the other localized in the vicinity of ter. Using a stochastic model that accounts for cell growth and divisions we demonstrate that shortening of the cell cycle can induce switching of the toggle to the state in which expression of the gene placed near ter is suppressed. The toggle bistability causes that the ratio of expression of the competing genes changes more than two orders of magnitude for a two-fold change of the doubling time. The increasing stability of the two toggle states enhances system sensitivity but also its reaction time.ConclusionsBy fusing the competing genes with fluorescent tags this mechanism could be tested and employed to create an indicator of the doubling time. By manipulating copy numbers of the competing genes and locus of the gene situated near ter, one can obtain equal average expression of both genes for any doubling time T between 20 and 120 min. Such a toggle would accurately report departures of the doubling time from T.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0483-4) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%

Genetic toggle switch controlled by bacterial growth rate

Jaruszewicz-Błońska

Lipniacki

2017

BMC Syst Biol

View full text Add to dashboard Cite

show abstract

“…Jaruszewicz et al (48) explicitly considered cell growth and division and found that the toggling rate of a genetic toggle switch is much higher in fast growing cells than that in slow growing cells. In addition, Veliz-Cuba et al (25) showed that the noise in division significantly increases the chance for state transitions just after the division. Although the effects of growth-induced protein dilution were included in both models, other growth-rate-dependent global effects (i.e., host-to-circuit coupling) such as transcription and translation were not explicitly considered.…”

Section: Discussionmentioning

confidence: 99%

“…Due to profound impacts upon synthetic and natural systems, circuit-host coupling has begun to be considered in recent modeling efforts. One key line of work has focused on incorporating more realistic host details, such as transcriptional delay and noise during the cell cycle, to understand possible circuit behaviors (24,25). Other modeling efforts have focused on the regulatory impacts of cell growth on gene expression.…”

Section: Introductionmentioning

confidence: 99%

Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch

Blanchard

Liao

2018

Biophysical Journal

View full text Add to dashboard Cite

Quantitative modeling of gene circuits is fundamentally important to synthetic biology, as it offers the potential to transform circuit engineering from trial-and-error construction to rational design and, hence, facilitates the advance of the field. Currently, typical models regard gene circuits as isolated entities and focus only on the biochemical processes within the circuits. However, such a standard paradigm is getting challenged by increasing experimental evidence suggesting that circuits and their host are intimately connected, and their interactions can potentially impact circuit behaviors. Here we systematically examined the roles of circuit-host coupling in shaping circuit dynamics by using a self-activating gene switch as a model circuit. Through a combination of deterministic modeling, stochastic simulation, and Fokker-Planck equation formalism, we found that circuit-host coupling alters switch behaviors across multiple scales. At the single-cell level, it slows the switch dynamics in the high protein production regime and enlarges the difference between stable steady-state values. At the population level, it favors cells with low protein production through differential growth amplification. Together, the two-level coupling effects induce both quantitative and qualitative modulations of the switch, with the primary component of the effects determined by the circuit's architectural parameters. This study illustrates the complexity and importance of circuit-host coupling in modulating circuit behaviors, demonstrating the need for a new paradigm-integrated modeling of the circuit-host system-for quantitative understanding of engineered gene networks.

show abstract

“…The perturbations due to the random partitioning of proteins at the time of cell division can have a strong effect on internal cell dynamics [27]. With metabolic loading internal and external fluctuations are even more strongly coupled.…”

Section: Discussionmentioning

confidence: 99%

Bistability and oscillations in co‐repressive synthetic microbial consortia

et al. 2017

Self Cite

View full text Add to dashboard Cite

Synthetic microbial consortia are conglomerations of multiple strains of genetically engineered microbes programmed to cooperatively bring about population-level phenotypes. By coordinating their activity, the constituent strains can display emergent behaviors that are difficult to engineer into isogenic populations. To do so, strains are engineered to communicate with one another through intercellular signaling pathways. As a result, the regulatory networks that control gene transcription throughout the population are sensitive to the extracellular concentration of the signaling molecules, and hence the relative densities of constituent strains. Here, we use computational modeling to examine how the behavior of a synthetic microbial consortium results from the interplay between the population dynamics governed by cell growth and the internal transcriptional dynamics governed by cell-to-cell signaling. Specifically, we examine a synthetic microbial consortium in which two strains each produce signals that down-regulate transcription in the other. Within a single strain this regulatory topology is called a “co-repressive toggle switch” and can lead to bistability. We find that in a two-strain synthetic microbial consortium the existence and stability of different states depends on the population-level dynamics of the interacting strains. As the two strains passively compete for space within the colony, their relative fractions can fluctuate and thus alter the strengths of intercellular signals. These fluctuations can drive the consortium to alternative equilibria. Additionally, if the growth rates of the strains depend on their transcriptional states, an additional feedback loop is created that can generate relaxation oscillations. These findings demonstrate that the dynamics of microbial consortia cannot be predicted from their regulatory topologies alone, but also is determined by interactions between the strains.

show abstract

Effects of cell cycle noise on excitable gene circuits

Cited by 5 publications

References 54 publications

Genetic toggle switch controlled by bacterial growth rate

Genetic toggle switch controlled by bacterial growth rate

Circuit-Host Coupling Induces Multifaceted Behavioral Modulations of a Gene Switch

Bistability and oscillations in co‐repressive synthetic microbial consortia

Contact Info

Product

Resources

About