Is cell size a spandrel?

Amir, Ariel

doi:10.7554/elife.22186

Cited by 50 publications

(64 citation statements)

References 46 publications

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“…The recent adder-per-origin model, an adaption of the Cooper-Helmstetter model, postulates that: (i) the time from initiation to division is constant regardless of cell size, and (ii) initiation occurs after a constant growth increment measured from the previous initiation (Figures 2D&S4; STAR Methods) [3, 7, 26]. Models that include initiation timing must account for the number of origins, because cells may initiate multiple rounds of replication before division.…”

Section: Resultsmentioning

confidence: 99%

A Parallel Adder Coordinates Mycobacterial Cell-Cycle Progression and Cell-Size Homeostasis in the Context of Asymmetric Growth and Organization

et al. 2017

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Summary In model bacteria, such as E. coli and B. subtilis, regulation of cell cycle progression and cellular organization achieves consistency in cell size, replication dynamics, and chromosome positioning [1–3]. Mycobacteria elongate and divide asymmetrically, giving rise to significant variation in cell size and elongation rate among closely related cells [4, 5]. Given the physical asymmetry of mycobacteria, the models that describe coordination of cellular organization and cell cycle progression in model bacteria are not directly translatable [1, 2, 6–8]. Here we used time-lapse microscopy and fluorescent reporters of DNA replication and chromosome positioning to examine the coordination of growth, division, and chromosome dynamics at a single-cell level in Mycobacterium smegmatis (M. smegmatis) and Mycobacterium bovis Bacillus Calmette–Guérin (BCG). By analyzing chromosome and replisome localization, we demonstrated that chromosome positioning is asymmetric and proportional to cell size. Furthermore, we found that cellular asymmetry is maintained throughout the cell cycle and is not established at division. Using measurements and stochastic modeling of mycobacterial cell size and cycle timing in both slow and fast growth conditions, we found that well-studied cell size control models are insufficient to explain the mycobacterial cell cycle. Instead, we showed that mycobacterial cell cycle progression is regulated by an unprecedented mechanism involving parallel adders (i.e. constant growth increments) that start at replication initiation. Together, these adders enable mycobacterial populations to regulate cell size, growth, and heterogeneity in the face of varying environments.

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Section: Resultsmentioning

confidence: 99%

A Parallel Adder Coordinates Mycobacterial Cell-Cycle Progression and Cell-Size Homeostasis in the Context of Asymmetric Growth and Organization

et al. 2017

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“…Theoretical models of stochastic gene expression have seldom considered cell division explicitly, and those which did considered a random generation time drawn from a preassigned distribution [40,41], or did not consider the time-dependence of transcription and translation rate [30,42]. The random generation time assumption is incompatible with the exponential growth of cell volume and protein numbers, because in the presence of noise it would lead to the divergence of cell size [43][44][45]. Here we take explicitly cell division into account and, for concreteness, use the "adder" model for cell division.…”

Section: Model Of Stochastic Gene Expressionmentioning

confidence: 99%

Homeostasis of protein and mRNA concentrations in growing cells

Lin

Amir

2018

Preprint

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Many experiments show that the concentrations of protein and mRNA fluctuate but on average are constant in growing cells, independent of the genome copy number. However, models of stochastic gene expression often assume constant gene expression rates that are proportional to the gene copy numbers, which are therefore incompatible with experiments. Here, we construct a minimal gene expression model to fill this gap. We show that (1) because the ribosomes translate all proteins, the concentrations of proteins are regulated in an exponentially growing cell volume; (2) the competition between genes for the RNA polymerases makes the gene expression rate independent of the genome number; (3) the fluctuations in ribosome level and cell density can generate a global extrinsic noise in protein concentrations; (4) correlations between mRNA and protein levels can be quantified.Despite the noisy nature of gene expression [1][2][3][4][5][6], various aspects of single cell dynamics, such as volume growth, are effectively deterministic. Recent single-cell measurements show that the growth of cell volumes is often exponential. These include bacteria [7][8][9][10], budding yeast [10][11][12][13][14] and mammalian cells [10,15]. Moreover, the mRNA and protein numbers are on average proportional to the cell volume throughout the cell cycle [16][17][18][19][20]. Therefore, the homeostasis of mRNA concentration and protein concentration is maintained in an exponentially growing cell volume. The exponential growths of mRNA and protein number indicate dynamical transcription and translation rates proportional to the cell volume, and also independent of the genome copy number. However, current gene expression models often assume a fixed cell volume with constant transcription and translation rates [1,5,[21][22][23], which are proportional to the gene copy number. Therefore, fixed cell volume models fail to reveal how cells keep constant mRNA and protein concentrations as the cell volume grows and the genome is replicated.The homeostasis of protein and mRNA concentrations imply that there must be a regulatory mechanism in place to prevent the accumulation of noise over time and to maintain a bounded distribution of concentrations. The goal of this work is to identify such a mechanism by developing a genome-wide coarse-grained model taking into account explicitly cell volume growth. We will consider an idealized cell in which genes are constitutively expressed for simplicity. The ubiquity of homeostasis suggests that the global machineries of gene expression, RNA polymerases (RNAPs) and ribosomes, should play a central role within the model. Indeed, as we will show later, the exponential growth of cell volume, protein and mRNA number originates from the auto-catalytic nature of ribosomes, the limiting factor in the translational process [24][25][26]. The bounded distributions of concentrations are a result of the fact that ribosomes make all proteins. The independence of the mRNA concentration of the genome copy number is a natural resul...

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“…The idea that nutrient-dependent increases in size may be an adaptation to multifork replication is further data indicating that C. crescentus, which does not undergo multifork replication, does not exhibit nutrient dependent increases in size (16). [For those interested in the topic, this hypothesis is addressed in depth here (4)]. An alternative hypothesis, is that increases in size provide a crude means of storing carbon and other nutrients in case nutritional fortunes suddenly change.…”

Section: Biosynthetic Capacity and Cell Sizementioning

confidence: 99%

Bacterial Cell Size: Multifactorial and Multifaceted

Westfall

Levin²

2017

Annu. Rev. Microbiol.

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How cells establish, maintain, and modulate size has always been an area of great interest and fascination. Until recently, technical limitations curtailed our ability to understand the molecular basis of bacterial cell size control. In the past decade, advances in microfluidics, imaging, and high throughput single cell analysis, however, have led to renewed interest in the topic and a flurry of work revealing size to be a highly complex trait involving the integration of three core aspects of bacterial physiology: metabolism, growth, and cell cycle progression.

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Is cell size a spandrel?

Cited by 50 publications

References 46 publications

A Parallel Adder Coordinates Mycobacterial Cell-Cycle Progression and Cell-Size Homeostasis in the Context of Asymmetric Growth and Organization

A Parallel Adder Coordinates Mycobacterial Cell-Cycle Progression and Cell-Size Homeostasis in the Context of Asymmetric Growth and Organization

Homeostasis of protein and mRNA concentrations in growing cells

Bacterial Cell Size: Multifactorial and Multifaceted

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