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A stochastic model correctly predicts changes in budding yeast cell cycle dynamics upon periodic expression of CLN2.

Oguz C, Palmisano A, Laomettachit T, Watson LT, Baumann WT, Tyson JJ - PLoS ONE (2014)

Bottom Line: Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model.We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression.These cells originate from daughters with extended budded periods due to size control during the budded period.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT
In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast.

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Cell size trajectories for successive mother and daughter cells.Data is collected during the simulations with three different periods of forced CLN2 expression: 90 min (A) and (B), 78 min (C) and (D), and 69 min (E) and (F). Shaded blue areas show the time intervals with forced expression (without delay in the MET3 turn-on/turn-off as in Figure 3C of [7]). Unbudded parts of the trajectories are plotted with red, budded parts are black, and thin black lines represent division events. The correct order of cell cycle events is enforced during the simulations (Table S9). Daughter simulations (marked with “D”) start from a daughter initial condition set, whereas mother simulations (marked with “M”) start from a mother initial condition set. These initial condition sets are extracted from the endpoints of 2000 min simulations with no forced CLN2 expression.
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pone-0096726-g007: Cell size trajectories for successive mother and daughter cells.Data is collected during the simulations with three different periods of forced CLN2 expression: 90 min (A) and (B), 78 min (C) and (D), and 69 min (E) and (F). Shaded blue areas show the time intervals with forced expression (without delay in the MET3 turn-on/turn-off as in Figure 3C of [7]). Unbudded parts of the trajectories are plotted with red, budded parts are black, and thin black lines represent division events. The correct order of cell cycle events is enforced during the simulations (Table S9). Daughter simulations (marked with “D”) start from a daughter initial condition set, whereas mother simulations (marked with “M”) start from a mother initial condition set. These initial condition sets are extracted from the endpoints of 2000 min simulations with no forced CLN2 expression.

Mentions: Figure 7 shows the cell size trajectories for mothers and daughters with pulses of 90, 78, and 69 min periods. In these simulations, no pedigrees are generated. Instead, we follow a single mother or daughter cell after each division. The mother initial conditions are from the end points of 2000 min cln3 mother simulations during which the fraction of cell mass retained after each division is a random number with a mean value of 0.58 and a standard deviation value of 0.029 (5% of the mean). Conversely, the daughter initial conditions come from the end points of cln3 simulations during which the fraction of cell mass retained after each division is the remainder of the total mass after the mother fraction is assigned. As seen in Figure 7A, budding events in daughter cycles are perfectly synchronized with 90 min period pulses, whereas the budding events show the same behavior in mother cycles (Figure 7F) when the pulse period is 69 min period (one budding event per pulse in both cases). On the other hand, daughters skip pulses three times with fast pulses (69 min forcing period in Figure 7E), whereas mothers exhibit multiple budding events four times with slow pulses (90 min forcing period in Figure 7B) in 1000 min simulations. The 78 min forcing period (Figures 7C and 7D) is a good compromise between the slow daughters and fast mothers that tend to stay behind or run ahead of the pulses. The results in Figures 7A–7F agree qualitatively with Figure 3C in [7].


A stochastic model correctly predicts changes in budding yeast cell cycle dynamics upon periodic expression of CLN2.

Oguz C, Palmisano A, Laomettachit T, Watson LT, Baumann WT, Tyson JJ - PLoS ONE (2014)

Cell size trajectories for successive mother and daughter cells.Data is collected during the simulations with three different periods of forced CLN2 expression: 90 min (A) and (B), 78 min (C) and (D), and 69 min (E) and (F). Shaded blue areas show the time intervals with forced expression (without delay in the MET3 turn-on/turn-off as in Figure 3C of [7]). Unbudded parts of the trajectories are plotted with red, budded parts are black, and thin black lines represent division events. The correct order of cell cycle events is enforced during the simulations (Table S9). Daughter simulations (marked with “D”) start from a daughter initial condition set, whereas mother simulations (marked with “M”) start from a mother initial condition set. These initial condition sets are extracted from the endpoints of 2000 min simulations with no forced CLN2 expression.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016136&req=5

pone-0096726-g007: Cell size trajectories for successive mother and daughter cells.Data is collected during the simulations with three different periods of forced CLN2 expression: 90 min (A) and (B), 78 min (C) and (D), and 69 min (E) and (F). Shaded blue areas show the time intervals with forced expression (without delay in the MET3 turn-on/turn-off as in Figure 3C of [7]). Unbudded parts of the trajectories are plotted with red, budded parts are black, and thin black lines represent division events. The correct order of cell cycle events is enforced during the simulations (Table S9). Daughter simulations (marked with “D”) start from a daughter initial condition set, whereas mother simulations (marked with “M”) start from a mother initial condition set. These initial condition sets are extracted from the endpoints of 2000 min simulations with no forced CLN2 expression.
Mentions: Figure 7 shows the cell size trajectories for mothers and daughters with pulses of 90, 78, and 69 min periods. In these simulations, no pedigrees are generated. Instead, we follow a single mother or daughter cell after each division. The mother initial conditions are from the end points of 2000 min cln3 mother simulations during which the fraction of cell mass retained after each division is a random number with a mean value of 0.58 and a standard deviation value of 0.029 (5% of the mean). Conversely, the daughter initial conditions come from the end points of cln3 simulations during which the fraction of cell mass retained after each division is the remainder of the total mass after the mother fraction is assigned. As seen in Figure 7A, budding events in daughter cycles are perfectly synchronized with 90 min period pulses, whereas the budding events show the same behavior in mother cycles (Figure 7F) when the pulse period is 69 min period (one budding event per pulse in both cases). On the other hand, daughters skip pulses three times with fast pulses (69 min forcing period in Figure 7E), whereas mothers exhibit multiple budding events four times with slow pulses (90 min forcing period in Figure 7B) in 1000 min simulations. The 78 min forcing period (Figures 7C and 7D) is a good compromise between the slow daughters and fast mothers that tend to stay behind or run ahead of the pulses. The results in Figures 7A–7F agree qualitatively with Figure 3C in [7].

Bottom Line: Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model.We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression.These cells originate from daughters with extended budded periods due to size control during the budded period.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT
In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast.

Show MeSH
Related in: MedlinePlus