Timing of gene expression in a cell‐fate decision system

Aymoz, Delphine; Solé, Carme; Pierre, J Talbot; Schmitt, Marta; Nadal, Eulàlia de; Posas, Francesc; Pelet, Serge

doi:10.15252/msb.20178024

Cited by 37 publications

(42 citation statements)

References 42 publications

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“…At the end of the indecisive phase, cells developed strong and stable polarity sites correctly oriented towards their partners, entering a “committed phase.” A similar stabilization of polarity clusters was noted in cells exposed to an artificial pheromone gradient [36]. Previous studies used the term commitment to indicate a change in MAPK activity [44] or mating pathway gene induction [63] occurring 15–30 min prior to fusion, and it seems probable that all of these changes are linked and that an increase in MAPK activity promotes commitment.…”

Section: Discussionmentioning

confidence: 55%

Ratiometric GPCR signaling enables directional sensing in yeast

et al. 2019

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Accurate detection of extracellular chemical gradients is essential for many cellular behaviors. Gradient sensing is challenging for small cells, which can experience little difference in ligand concentrations on the up-gradient and down-gradient sides of the cell. Nevertheless, the tiny cells of the yeast Saccharomyces cerevisiae reliably decode gradients of extracellular pheromones to find their mates. By imaging the behavior of polarity factors and pheromone receptors, we quantified the accuracy of initial polarization during mating encounters. We found that cells bias the orientation of initial polarity up-gradient, even though they have unevenly distributed receptors. Uneven receptor density means that the gradient of ligand-bound receptors does not accurately reflect the external pheromone gradient. Nevertheless, yeast cells appear to avoid being misled by responding to the fraction of occupied receptors rather than simply the concentration of ligand-bound receptors. Such ratiometric sensing also serves to amplify the gradient of active G protein. However, this process is quite error-prone, and initial errors are corrected during a subsequent indecisive phase in which polarity clusters exhibit erratic mobile behavior.

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Section: Discussionmentioning

confidence: 55%

Ratiometric GPCR signaling enables directional sensing in yeast

et al. 2019

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“…Here, the question we are interested in is how feedback strength represented by c affects the timing of intracellular events (in fact, the expression level of the protein). We may assume that c changes in the interval of 4 10 1 − due to our setting. In order to find the optimal feedback mechanism, our strategy is to change ( ) Fig.…”

Section: Optimal Feedback Control Strategymentioning

confidence: 99%

“…The timing of intracellular events is pivotal for many cellular processes, ranging from cellular responses to external stimuli to cell fate decision (1)(2)(3)(4)(5)(6)(7)(8), cell differentiation (9)(10)(11), cell apoptosis (1， 12,13), and cell cycle (14)(15)(16)(17)(18). For example, an activated gene may be required to reach in a precise time a threshold level of the regulatory protein expression that triggers a particular downstream signal pathway (16,19,20).…”

Section: Introductionmentioning

confidence: 99%

Control strategies for the timing of intracellular events

Cao

Qiu

Zhang

2019

Preprint

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While the timing of intracellular events is essential for many cellular processes, gene expression inside a cell can exhibit substantial cell-to-cell variability, raising the question of how cells ensure precision in the event timing despite such stochasticity. We address this question by analyzing a biologically reasonable model of gene expression in the context of first passage time (FPT), focusing on two experimentally measurable statistics: mean FPT (MFPT) and timing variability (TV). We show that: (1) transcriptional burst size (BS) and burst frequency (BF) can minimize the TV; (2) translational BS monotonically reduces the MFPT to a nonzero low bound and can minimize the TV; (3) the timescale of promoter kinetics can minimize both the MFPT and the TV, depending on the ratio of the off-switching rate over the on-switching rate; and (4) positive feedback regulation of any form can all minimize the TV, whereas negative feedback regulation of transcriptional BF or BS always enhances the TV. These control strategies can have broad implications for diverse cellular processes relying on precise temporal triggering of events.

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“…On the one hand, 2 some important cellular processes depend on precision in the timing of key intracellular 3 events, e.g., cell fate decision presumably requires a precise control of gene expression 4 timing [2][3][4][5][6][7][8][9][10][11][12][13][14][15], and the controls of cell cycle and circadian clocks require timing precision 5 that can be crucial for the correct physiology [16][17][18][19][20][21][22][23][24]. Most of these processes are based 6 on gene expression, e.g., an activated gene may be required to reach in a precise time threshold level of p53 to execute apoptosis and this threshold increases with time [26].…”

mentioning

confidence: 99%

“…Most of these processes are based 6 on gene expression, e.g., an activated gene may be required to reach in a precise time threshold level of p53 to execute apoptosis and this threshold increases with time [26]. 13 Similarly, fractional killing of a cancer cell population by chemotherapy depends on 14 arrival time: the shorter the arrival time is, the more are the cells killed, indicating 15 the therapeutic efficacy is better. In short, timing precision and arrival time are two 16 important indices measuring the event timing.…”

mentioning

confidence: 99%

Dynamic variability in apoptotic threshold as a strategy for combating fractional killing

Qiu

Zhang

2018

Preprint

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Timing of events, which is essential for many cellular processes, depends on regulatory proteins reaching a critical threshold that in general is dynamically fluctuating due to molecular interactions. Increasing evidence shows considerable cell-to-cell variation in the timing of key intracellular events among isogenic cells, but how expression noise and threshold fluctuations impact both threshold crossing and timing precision remain elusive. Here we first formulate stochastic temporal timing of events as a problem of the first passage time (FPT) to a fluctuating threshold and then transform this problem into a higher-dimensional FPT problem with some fixed threshold. Using a stochastic model of gene regulation, we show that (1) in contrast to the case of fixed threshold, threshold fluctuations can both accelerate response (i.e., shorten the time of threshold crossing) and raise timing precision (i.e., reduce timing variability), (2) there is an optimal mean burst size such that the timing precision is best, and (3) fast threshold fluctuations can perform better in accelerating response and reducing variability than slow threshold fluctuations. These results not only interpret recent experimental observations but also have broad implications for diverse cellular processes and in drug therapy.July22, 2018 1/33 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/375915 doi: bioRxiv preprint first posted online Jul. 24, 2018; Author summaryIncreasing evidence shows substantial cell-to-cell variation in the timing of key intracellular events among isogenic cells, which has potential consequences on cellular functions and phenotypes. In general, this variation originates from the stochasticity of two different kinds: gene expression noise that is inherent due to low copy numbers and threshold fluctuations that are generated due to molecular interactions. However, it is unclear how these stochastic origins impact precision in the event timing and the time that regulatory proteins reach threshold levels (called arrival time). In order to reveal this impact, we perform analytical and numerical calculations for the first passage time distributions in a representative stochastic model of gene regulation where an event is triggered when the protein level crosses a dynamically fluctuating threshold. Counterintuitively, we find that fluctuating thresholds not only shorten arrival time but also raise timing precision in contrast to fixed thresholds, and fast threshold fluctuations can both shorten arrival time and reduce timing variability than slow threshold fluctuations. These findings can well explain recent experimental observations such as fractional killing of a cell population, cell apoptosis induced by dynamics of p53 in response to chemotherapy, and dynamic persistence of bacteria.

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Timing of gene expression in a cell‐fate decision system

Cited by 37 publications

References 42 publications

Ratiometric GPCR signaling enables directional sensing in yeast

Ratiometric GPCR signaling enables directional sensing in yeast

Control strategies for the timing of intracellular events

Dynamic variability in apoptotic threshold as a strategy for combating fractional killing

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