Constriction rate modulation can drive cell size control and homeostasis inC. crescentus

AbstractRod-shaped bacteria typically grow first via sporadic and dispersed elongation along their lateral walls, then via a combination of zonal elongation and constriction at the division site to form the poles of daughter cells. Although constriction comprises up to half of the cell cycle, its impact on cell size control and homeostasis has rarely been considered. To reveal the roles of cell elongation and constriction in bacterial size regulation during cell division, we captured the shape dynamics ofCaulobacter crescentuswith time-lapse structured illumination microscopy and used molecular markers as cell-cycle landmarks. We perturbed constriction rate using a hyperconstriction mutant or fosfomycin inhibition. We report that constriction rate contributes to both size control and homeostasis, by determining elongation during constriction, and by compensating for variation in pre-constriction elongation on a single-cell basis.

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Characterizing non-exponential growth and bimodal cell size distributions in Schizosaccharomyces pombe: an analytical approach

10.1101/2021.06.10.447927 ◽

2021 ◽

Author(s):

Chen Jia ◽

Abhyudai Singh ◽

Ramon Grima

Keyword(s):

Cell Cycle ◽

Fission Yeast ◽

Cell Size ◽

Control Strategy ◽

Size Control ◽

Birth Size ◽

Size Distributions ◽

Cell Size Distribution ◽

A Cell ◽

Cell Size Control

Unlike many single-celled organisms, the growth of fission yeast cells within a cell cycle is not exponential. It is rather characterized by three distinct phases (elongation, septation and fission), each with a different growth rate. Experiments also show that the distribution of cell size in a lineage is often bimodal, unlike the unimodal distributions measured for the bacterium Escherichia coli. Here we construct a detailed stochastic model of cell size dynamics in fission yeast. The theory leads to analytic expressions for the cell size and the birth size distributions, and explains the origin of bimodality seen in experiments. In particular our theory shows that the left peak in the bimodal distribution is associated with cells in the elongation phase while the right peak is due to cells in the septation and fission phases. We show that the size control strategy, the variability in the added size during a cell cycle and the fraction of time spent in each of the three cell growth phases have a strong bearing on the shape of the cell size distribution. Furthermore we infer all the parameters of our model by matching the theoretical cell size and birth size distributions to those from experimental single cell time-course data for seven different growth conditions. Our method provides a much more accurate means of determining the cell size control strategy (timer, adder or sizer) than the standard method based on the slope of the best linear fit between the birth and division sizes. We also show that the variability in added size and the strength of cell size control of fission yeast depend weakly on the temperature but strongly on the culture medium.

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Analysis of noise mechanisms in cell size control

10.1101/080465 ◽

2016 ◽

Cited By ~ 2

Author(s):

Saurabh Modi ◽

Cesar A. Vargas-Garcia ◽

Khem Raj Ghusinga ◽

Abhyudai Singh

Keyword(s):

Cell Size ◽

Power Law ◽

Caulobacter Crescentus ◽

Control Strategies ◽

Size Control ◽

Cellular Growth ◽

Power Law Distribution ◽

Noise Sources ◽

Cell Size Distribution ◽

Cell Size Control

AbstractAt the single-cell level, noise features in multiple ways through the inherent stochasticity of biomolecular processes, random partitioning of resources at division, and fluctuations in cellular growth rates. How these diverse noise mechanisms combine to drive variations in cell size within an isoclonal population is not well understood. To address this problem, we systematically investigate the contributions of different noise sources in well-known paradigms of cell-size control, such as the adder (division occurs after adding a fixed size from birth) and the sizer (division occurs upon reaching a size threshold). Analysis reveals that variance in cell size is most sensitive to errors in partitioning of volume among daughter cells, and not surprisingly, this process is well regulated among microbes. Moreover, depending on the dominant noise mechanism, different size control strategies (or a combination of them) provide efficient buffering of intercellular size variations. We further explore mixer models of size control, where a timer phase precedes/follows an adder, as has been proposed inCaulobacter crescentus. While mixing a timer with an adder can sometimes attenuate size variations, it invariably leads to higher-order moments growing unboundedly over time. This results in the cell size following a power-law distribution with an exponent that is inversely dependent on the noise in the timer phase. Consistent with theory, we find evidence of power-law statistics in the tail ofC. crescentuscell-size distribution, but there is a huge discrepancy in the power-law exponent as estimated from data and theory. However, the discrepancy is removed after data reveals that the size added by individual newborns from birth to division itself exhibits power-law statistics. Taken together, this study provides key insights into the role of noise mechanisms in size homeostasis, and suggests an inextricable link between timer-based models of size control and heavy-tailed cell size distributions.

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Initiation of chromosome replication controls both division and replication cycles in E. coli through a double-adder mechanism

10.1101/593590 ◽

2019 ◽

Author(s):

Guillaume Witz ◽

Erik van Nimwegen ◽

Thomas Julou

Keyword(s):

Cell Cycle ◽

Cell Size ◽

Cell Cycle Control ◽

Size Control ◽

Time Lapse ◽

Growth Conditions ◽

Replication Initiation ◽

Stochastic Simulations ◽

E Coli ◽

Wide Range

AbstractLiving cells proliferate by completing and coordinating two essential cycles, a division cycle that controls cell size, and a DNA replication cycle that controls the number of chromosomal copies in the cell. Despite lacking dedicated cell cycle control regulators such as cyclins in eukaryotes, bacteria such as E. coli manage to tightly coordinate those two cycles across a wide range of growth conditions, including situations where multiple nested rounds of replication progress simultaneously. Various cell cycle models have been proposed to explain this feat, but it has been impossible to validate them so far due to a lack of experimental tools for systematically testing their different predictions. Recently new insights have been gained on the division cycle through the study of the structure of fluctuations in growth, size, and division in individual cells. In particular, it was found that cell size appears to be controlled by an adder mechanism, i.e. the added volume between divisions is held approximately constant and fluctuates independently of growth rate and cell size at birth. However, how replication initiation is regulated and coupled to cell size control remains unclear, mainly due to scarcity of experimental measurements on replication initiation at the single-cell level. Here, we used time-lapse microscopy in combination with microfluidics to directly measure growth, division and replication in thousands of single E. coli cells growing in both slow and fast growth conditions. In order to compare different phenomenological models of the cell cycle, we introduce a statistical framework which assess their ability to capture the correlation structure observed in the experimental data. Using this in combination with stochastic simulations, our data indicate that, instead of thinking of the cell cycle as running from birth to division, the cell cycle is controlled by two adder mechanisms starting at the initiation of replication: the added volume since the last initiation event controls the timing of both the next division event and the next replication initiation event. Interestingly the double-adder mechanism identified in this study has recently been found to explain the more complex cell cycle of mycobacteria, suggesting shared control strategies across species.

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Quantitative examination of five stochastic cell-cycle and cell-size control models for Escherichia coli and Bacillus subtilis

10.1101/2021.06.06.447266 ◽

2021 ◽

Author(s):

Guillaume Le Treut ◽

Fangwei Si ◽

Dongyang Li ◽

Suckjoon Jun

Keyword(s):

Experimental Data ◽

Escherichia Coli ◽

Cell Cycle ◽

Bacillus Subtilis ◽

Cell Size ◽

Size Control ◽

Statistical Analysis Method ◽

Quantitative Examination ◽

Cell Size Control ◽

Bacterial Cell Cycle

We examine five quantitative models of the cell-cycle and cell-size control in Escherichia coli and Bacillus subtilis that have been proposed over the last decade to explain single-cell experimental data generated with high-throughput methods. After presenting the statistical properties of these models, we test their predictions against experimental data. Based on simple calculations of the defining correlations in each model, we first dismiss the stochastic Helmstetter-Cooper model and the Initiation Adder model, and show that both the Replication Double Adder and the Independent Double Adder model are more consistent with the data than the other models. We then apply a recently proposed statistical analysis method and obtain that the Independent Double Adder model is the most likely model of the cell cycle. By showing that the Replication Double Adder model is fundamentally inconsistent with size convergence by the adder principle, we conclude that the Independent Double Adder model is most consistent with the data and the biology of bacterial cell-cycle and cell-size control. Mechanistically, the Independent Adder Model is equivalent to two biological principles: (i) balanced biosynthesis of the cell-cycle proteins, and (ii) their accumulation to a respective threshold number to trigger initiation and division.

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Cell size control driven by the circadian clock and environment in cyanobacteria

10.1101/183558 ◽

2017 ◽

Cited By ~ 4

Author(s):

Bruno M. C. Martins ◽

Amy K. Tooke ◽

Philipp Thomas ◽

James C. W. Locke

Keyword(s):

Cell Division ◽

Circadian Clock ◽

Cell Size ◽

Size Control ◽

Time Lapse ◽

Complex Interactions ◽

Light Levels ◽

Subjective Night ◽

In The Wild ◽

Cell Size Control

AbstractHow cells maintain their size has been extensively studied under constant conditions. In the wild, however, cells rarely experience constant environments. Here, we examine how the 24-hour circadian clock and environmental cycles modulate cell size control and division timings in the cyanobacteriumSynechococcus elongatususing single-cell time-lapse microscopy. Under constant light, wild type cells follow an apparent sizer-like principle. Closer inspection reveals that the clock generates two subpopulations, with cells born in the subjective day following different division rules from cells born in subjective night. A stochastic model explains how this behaviour emerges from the interaction of cell size control with the clock. We demonstrate that the clock continuously modulates the probability of cell division throughout day and night, rather than solely applying an on-off gate to division as previously proposed. Iterating between modelling and experiments, we go on to show that the combined effects of the environment and the clock on cell division are explained by an effective coupling function. Under naturally graded light-dark cycles, this coupling shifts cell division away from dusk and dawn, when light levels are low and cell growth is reduced. Our analysis allows us to disentangle, and predict the effects of, the complex interactions between the environment, clock, and cell size control.

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Cell-cycle-specific F plasmid replication: regulation by cell size control of initiation.

Journal of Bacteriology ◽

10.1128/jb.173.8.2673-2680.1991 ◽

1991 ◽

Vol 173 (8) ◽

pp. 2673-2680 ◽

Cited By ~ 22

Author(s):

J D Keasling ◽

B O Palsson ◽

S Cooper

Keyword(s):

Cell Cycle ◽

Cell Size ◽

Size Control ◽

Plasmid Replication ◽

F Plasmid ◽

Replication Regulation ◽

Cell Size Control

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Cell size control driven by the circadian clock and environment in cyanobacteria

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1811309115 ◽

2018 ◽

Vol 115 (48) ◽

pp. E11415-E11424 ◽

Cited By ~ 19

Author(s):

Bruno M. C. Martins ◽

Amy K. Tooke ◽

Philipp Thomas ◽

James C. W. Locke

Keyword(s):

Cell Division ◽

Circadian Clock ◽

Cell Size ◽

Time Window ◽

Size Control ◽

Time Lapse ◽

Time Of Day ◽

Division Rate ◽

Cell Size Control ◽

And Shifts

How cells maintain their size has been extensively studied under constant conditions. In the wild, however, cells rarely experience constant environments. Here, we examine how the 24-h circadian clock and environmental cycles modulate cell size control and division timings in the cyanobacteriumSynechococcus elongatususing single-cell time-lapse microscopy. Under constant light, wild-type cells follow an apparent sizer-like principle. Closer inspection reveals that the clock generates two subpopulations, with cells born in the subjective day following different division rules from cells born in subjective night. A stochastic model explains how this behavior emerges from the interaction of cell size control with the clock. We demonstrate that the clock continuously modulates the probability of cell division throughout day and night, rather than solely applying an on−off gate to division, as previously proposed. Iterating between modeling and experiments, we go on to identify an effective coupling of the division rate to time of day through the combined effects of the environment and the clock on cell division. Under naturally graded light−dark cycles, this coupling narrows the time window of cell divisions and shifts divisions away from when light levels are low and cell growth is reduced. Our analysis allows us to disentangle, and predict the effects of, the complex interactions between the environment, clock, and cell size control.

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A bimolecular mechanism for the cell size control of the cell cycle

Biosystems ◽

10.1016/0303-2647(83)90012-6 ◽

1983 ◽

Vol 16 (3-4) ◽

pp. 297-305 ◽

Cited By ~ 15

Author(s):

L. Alberghina ◽

E. Martegani ◽

L. Mariani ◽

G. Bortolan

Keyword(s):

Cell Cycle ◽

Cell Size ◽

Size Control ◽

Cell Size Control ◽

Bimolecular Mechanism

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Quantitative Examination of Five Stochastic Cell-Cycle and Cell-Size Control Models for Escherichia coli and Bacillus subtilis

Frontiers in Microbiology ◽

10.3389/fmicb.2021.721899 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guillaume Le Treut ◽

Fangwei Si ◽

Dongyang Li ◽

Suckjoon Jun

Keyword(s):

Experimental Data ◽

Escherichia Coli ◽

Cell Cycle ◽

Bacillus Subtilis ◽

Cell Size ◽

Size Control ◽

Statistical Analysis Method ◽

Quantitative Examination ◽

Cell Size Control ◽

Bacterial Cell Cycle

We examine five quantitative models of the cell-cycle and cell-size control in Escherichia coli and Bacillus subtilis that have been proposed over the last decade to explain single-cell experimental data generated with high-throughput methods. After presenting the statistical properties of these models, we test their predictions against experimental data. Based on simple calculations of the defining correlations in each model, we first dismiss the stochastic Helmstetter-Cooper model and the Initiation Adder model, and show that both the Replication Double Adder (RDA) and the Independent Double Adder (IDA) model are more consistent with the data than the other models. We then apply a recently proposed statistical analysis method and obtain that the IDA model is the most likely model of the cell cycle. By showing that the RDA model is fundamentally inconsistent with size convergence by the adder principle, we conclude that the IDA model is most consistent with the data and the biology of bacterial cell-cycle and cell-size control. Mechanistically, the Independent Adder Model is equivalent to two biological principles: (i) balanced biosynthesis of the cell-cycle proteins, and (ii) their accumulation to a respective threshold number to trigger initiation and division.

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