scholarly journals A note on noise suppression in cell-size control

2017 ◽  
Author(s):  
Abhyudai Singh
Keyword(s):  
Cell Division ◽  
Cell Size ◽  
Noise Suppression ◽  
Essential Feature ◽  
Size Control ◽  
Cell Types ◽  
Cellular Growth ◽  
Model Parameters ◽  
Division Rate ◽  
Newborn Size

AbstractDiverse cell types employ mechanisms to maintain size homeostasis and minimize aberrant fluctuations in cell size. It is well known that exponential cellular growth can drive unbounded intercellular variations in cell size, if the timing of cell division is size independent. Hence coupling of division timing to size is an essential feature of size control. We formulate a stochastic model, where exponential cellular growth is coupled with random cell division events, and the rate at which division events occur increases as a power function of cell size. Interestingly, in spite of nonlinearities in the stochastic dynamical model, statistical moments of the newborn cell size can be determined in closed form, providing fundamental limits to suppression of size fluctuations. In particular, formulas reveal that the magnitude of fluctuations in the newborn size is determined by the inverse of the size exponent in the division rate, and this relationship is independent of other model parameters, such as the growth rate. We further expand these results to consider randomness in the partitioning of mother cell size among daughters at the time of division. The sensitivity of newborn size fluctuations to partitioning noise is found to monotonically decrease, and approach a non-zero value, with increasing size exponent in the division rate. Finally, we discuss how our analytical results provide limits on noise control in commonly used models for cell size regulation.

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

2018 ◽  
Vol 115 (48) ◽  
pp. E11415-E11424 ◽  
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.

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

scholarly journals Cell size regulation in bacteria

2014 ◽  
Author(s):  
Ariel Amir
Keyword(s):  
Cell Size ◽  
Narrow Range ◽  
Size Control ◽  
Exponential Dependence ◽  
Model Parameters ◽  
E Coli ◽  
Daughter Cells ◽  
Mother And Daughter ◽  
A Cell ◽  
Initiation Of Dna Replication

Various bacteria such as the canonical gram negative Escherichia coli or the well-studied gram positive Bacillus subtilis divide symmetrically after they approximately double their volume. Their size at division is not constant, but is typically distributed over a narrow range. Here, we propose an analytically tractable model for cell size control, and calculate the cell size and inter-division time distributions, and the correlations between these variables. We suggest ways of extracting the model parameters from experimental data, and show that existing data for E. coli supports partial size control, and a particular explanation: a cell attempts to add a constant volume from the time of initiation of DNA replication to the next initiation event. This hypothesis accounts for the experimentally observed correlations between mother and daughter cells as well as the exponential dependence of size on growth rate.

scholarly journals Hybrid systems approach to modeling stochastic dynamics of cell size

2016 ◽  
Author(s):  
Cesar Augusto Vargas-Garcia ◽  
Abhyudai Singh
Keyword(s):  
Growth Rate ◽  
Cell Size ◽  
Size Variation ◽  
Model Parameters ◽  
Constant Growth Rate ◽  
Division Rate ◽  
Size Dependent ◽  
Daughter Cells ◽  
Constant Growth ◽  
Over Time

A ubiquitous feature of all living cells is their growth over time followed by division into two daughter cells. How a population of genetically identical cells maintains size homeostasis, i.e., a narrow distribution of cell size, is an intriguing fundamental problem. We model size using a stochastic hybrid system, where a cell grows exponentially over time and probabilistic division events are triggered at discrete time intervals. Moreover, whenever these events occur, size is randomly partitioned among daughter cells. We first consider a scenario, where a timer (i.e., cell-cycle clock) that measures the time since the last division event regulates cellular growth and the rate of cell division. Analysis reveals that such a timer-driven system cannot achieve size homeostasis, in the sense that, the cell-to-cell size variation grows unboundedly with time. To explore biologically meaningful mechanisms for controlling size we consider three different classes of models: i) a size-dependent growth rate and timer-dependent division rate; ii) a constant growth rate and size-dependent division rate and iii) a constant growth rate and division rate that depends both on the cell size and timer. We show that each of these strategies can potentially achieve bounded intercellular size variation, and derive closed-form expressions for this variation in terms of underlying model parameters. Finally, we discuss how different organisms have adopted the above strategies for maintaining cell size homeostasis.

scholarly journals A new class of cyclin dependent kinase in Chlamydomonas is required for coupling cell size to cell division

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yubing Li ◽  
Dianyi Liu ◽  
Cristina López-Paz ◽  
Bradley JSC Olson ◽  
James G Umen
Keyword(s):  
Cell Division ◽  
Cell Size ◽  
Mother Cell ◽  
Size Control ◽  
Mitotic Division ◽  
General Mechanism ◽  
Cell Cycle Regulators ◽  
Proliferating Cells ◽  
Multiple Fission ◽  
Division Number

Proliferating cells actively control their size by mechanisms that are poorly understood. The unicellular green alga Chlamydomonas reinhardtii divides by multiple fission, wherein a ‘counting’ mechanism couples mother cell-size to cell division number allowing production of uniform-sized daughters. We identified a sizer protein, CDKG1, that acts through the retinoblastoma (RB) tumor suppressor pathway as a D-cyclin-dependent RB kinase to regulate mitotic counting. Loss of CDKG1 leads to fewer mitotic divisions and large daughters, while mis-expression of CDKG1 causes supernumerous mitotic divisions and small daughters. The concentration of nuclear-localized CDKG1 in pre-mitotic cells is set by mother cell size, and its progressive dilution and degradation with each round of cell division may provide a link between mother cell-size and mitotic division number. Cell-size-dependent accumulation of limiting cell cycle regulators such as CDKG1 is a potentially general mechanism for size control.

scholarly journals Analysis of noise mechanisms in cell size control

2016 ◽  
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.

scholarly journals Division rate, cell size and proteome allocation: impact on gene expression noise and implications for the dynamics of genetic circuits

2017 ◽  
Author(s):  
François Bertaux ◽  
Samuel Marguerat ◽  
Vahid Shahrezaei
Keyword(s):  
Gene Expression ◽  
Cell Division ◽  
Cell Size ◽  
Global Changes ◽  
Noise Levels ◽  
Division Rate ◽  
Gene Expression Noise ◽  
Expression Noise ◽  
Cell Division Rate ◽  
Degradation Rates

AbstractThe cell division rate, size, and gene expression programmes change in response to external conditions. These global changes impact on average concentrations of biomolecule and their variability or noise. Gene expression is inherently stochastic, and noise levels of individual proteins depend on synthesis and degradation rates as well as on cell-cycle dynamics. We have modelled stochastic gene expression inside growing and dividing cells to study the effect of division rates on noise in mRNA and protein expression. We use assumptions and parameters relevant to Escherichia coli, for which abundant quantitative data are available. We find that coupling of transcription, but not translation rates to the rate of cell division can result in protein concentration and noise homeostasis across conditions. Interestingly, we find that the increased cell size at fast division rates, observed in E. coli d other unicellular organisms, buffers noise levels even for proteins with decreased expression at faster growth. We then investigate the functional importance of these regulations using gene regulatory networks that exhibit bi-stability and oscillations. We find that network topology affects robustness to changes in division rate in complex and unexpected ways. In particular, a simple model of persistence, based on global physiological feedback, predicts increased proportion of persistors cells at slow division rates. Altogether, our study reveals how cell size regulation in response to cell division rate could help controlling gene expression noise. It also highlights that understanding of circuits’ robustness across growth conditions is key for the effective design of synthetic biological systems.

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