Abstract
BackgroundGene expression within cells is known to fluctuate stochastically in time. However, the origins of gene expression noise remain incompletely understood. The bacterial cell cycle has been suggested as one source, involving chromosome replication, exponential volume growth, and various other changes in cellular composition. Elucidating how these factors give rise to expression variations is important to models of cellular homeostasis, fidelity of signal transmission, and cell-fate decisions.ResultsUsing single-cell time-lapse microscopy, we measured cellular growth as well as fluctuations in the expression rate of a fluorescent protein and its concentration. We found that, within the population, the mean expression rate doubles throughout the cell cycle with a characteristic cell cycle phase dependent shape which is different for slow and fast growth rates. At low growth rate, we find the mean expression rate was initially flat, and then rose approximately linearly by a factor two until the end of the cell cycle. The mean concentration fluctuated at low amplitude with sinusoidal-like dependence on cell cycle phase. Traces of individual cells were consistent with a sudden two-fold increase in expression rate, together with other non-cell cycle noise. A model was used to relate the findings and to explain the cell cycle-induced variations for different chromosomal positions.ConclusionsWe found that the bacterial cell cycle contribution to expression noise consists of two parts: a deterministic oscillation in synchrony with the cell cycle and a stochastic component caused by variable timing of gene replication. Together, they cause half of the expression rate noise. Concentration fluctuations are partially suppressed by a noise cancelling mechanism that involves the exponential growth of cellular volume. A model explains how the functional form of the concentration oscillations depends on chromosome position.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0231-z) contains supplementary material, which is available to authorized users.
Highlights
Gene expression within cells is known to fluctuate stochastically in time
Taking the data for all cells with a completed cell cycle (n = 393) over all cell cycle phases, the protein expression rate displayed a total noise intensity of 0.48 [17]
An initially constant rate and two-fold increase is consistent with the known chromosome replication pattern for the observed mean growth rate (0.6 dbl/h): a single chromosome copy in the first period of the cell cycle, after which replication occurs in the second period that produces two copies [29]
Summary
Gene expression within cells is known to fluctuate stochastically in time. the origins of gene expression noise remain incompletely understood. The bacterial cell cycle has been suggested as one source, involving chromosome replication, exponential volume growth, and various other changes in cellular composition Elucidating how these factors give rise to expression variations is important to models of cellular homeostasis, fidelity of signal transmission, and cell-fate decisions. Single-cell investigations of Saccharomyces cerevisiae have shown quasi-periodic fluctuations of protein expression rates [20] and concentrations [21] in synchrony with the cell cycle. Direct experimental investigations of the impact of the bacterial cell cycle on expression variability are lacking Elucidating this question is important to understand the origins of gene expression noise, modeling of genetic circuits, and resulting impact on growth variability [28] as well as other forms of cellular heterogeneity [10]
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