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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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Simulated return maps for successive cells with and without forced CLN2 expression.No forcing is applied in (A) and (C), whereas the forcing period is 90 min in (B) and (D). “D” and “M” stand for daughters and mothers, respectively. Each map divides the 0–90 min time interval into 20 equally sized subintervals. Colors represent the fraction of data points in each map region as depicted in the color map on the right. Only the bright colors of this map are used in the return maps except for the map regions with very low data density. Lines  are depicted in yellow. Each return map is made using the data collected from eight independently generated pedigrees.
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pone-0096726-g004: Simulated return maps for successive cells with and without forced CLN2 expression.No forcing is applied in (A) and (C), whereas the forcing period is 90 min in (B) and (D). “D” and “M” stand for daughters and mothers, respectively. Each map divides the 0–90 min time interval into 20 equally sized subintervals. Colors represent the fraction of data points in each map region as depicted in the color map on the right. Only the bright colors of this map are used in the return maps except for the map regions with very low data density. Lines are depicted in yellow. Each return map is made using the data collected from eight independently generated pedigrees.

Mentions: Figure 4 compares the return maps (with period of 90 min) generated with forced CLN2 expression (cln3 MET3-CLN2) against the control maps (cln3). According to Figure 4B, half of the daughters (red map region with 0.5 data density) are on the diagonal at 30 min. These daughter cells are so called “locked cells” [7] since they are synchronized with the pulses of CLN2 expression. Similar to Figure 2C in [7] (bottom left map), about 300 data points are visualized on this map. On the other hand, the return map for successive mothers with 90 min of forced CLN2 expression (Figure 4D) show that only about 10% of the mothers (map region with 0.1 data density) are on the diagonal, whereas the majority are below the diagonal since the mother cycles are significantly faster than the incoming pulses (). Figures 4A and 4C show the corresponding daughter and mother control maps, respectively. Both have low density map regions in striking contrast with the higher density map regions in Figures 4B and 4D. In the control maps, daughters are spread over the whole map, whereas mothers are mostly below the diagonal. Simulation results shown in Figure 4 qualitatively agree with Figure 2C in [7] that illustrates the experimental results (cln3 versus cln3 MET3-CLN2 maps) under the same conditions.


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)

Simulated return maps for successive cells with and without forced CLN2 expression.No forcing is applied in (A) and (C), whereas the forcing period is 90 min in (B) and (D). “D” and “M” stand for daughters and mothers, respectively. Each map divides the 0–90 min time interval into 20 equally sized subintervals. Colors represent the fraction of data points in each map region as depicted in the color map on the right. Only the bright colors of this map are used in the return maps except for the map regions with very low data density. Lines  are depicted in yellow. Each return map is made using the data collected from eight independently generated pedigrees.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0096726-g004: Simulated return maps for successive cells with and without forced CLN2 expression.No forcing is applied in (A) and (C), whereas the forcing period is 90 min in (B) and (D). “D” and “M” stand for daughters and mothers, respectively. Each map divides the 0–90 min time interval into 20 equally sized subintervals. Colors represent the fraction of data points in each map region as depicted in the color map on the right. Only the bright colors of this map are used in the return maps except for the map regions with very low data density. Lines are depicted in yellow. Each return map is made using the data collected from eight independently generated pedigrees.
Mentions: Figure 4 compares the return maps (with period of 90 min) generated with forced CLN2 expression (cln3 MET3-CLN2) against the control maps (cln3). According to Figure 4B, half of the daughters (red map region with 0.5 data density) are on the diagonal at 30 min. These daughter cells are so called “locked cells” [7] since they are synchronized with the pulses of CLN2 expression. Similar to Figure 2C in [7] (bottom left map), about 300 data points are visualized on this map. On the other hand, the return map for successive mothers with 90 min of forced CLN2 expression (Figure 4D) show that only about 10% of the mothers (map region with 0.1 data density) are on the diagonal, whereas the majority are below the diagonal since the mother cycles are significantly faster than the incoming pulses (). Figures 4A and 4C show the corresponding daughter and mother control maps, respectively. Both have low density map regions in striking contrast with the higher density map regions in Figures 4B and 4D. In the control maps, daughters are spread over the whole map, whereas mothers are mostly below the diagonal. Simulation results shown in Figure 4 qualitatively agree with Figure 2C in [7] that illustrates the experimental results (cln3 versus cln3 MET3-CLN2 maps) under the same conditions.

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