Fig 1.
Overview of cell cycle dynamics in changing environments.
(A) Schematic of environmental control of the cell cycle, involving direct regulation through signalling pathways and indirect effects through growth. (B) Cell cycle progression and growth. Cells grow isotropically for the duration of G1 (TG1), before polarising growth to a bud for the remainder of the cell cycle (TS/G2/M). The daughter cell size is determined by the bud size at division. (C) Simulation of cell cycle dynamics in the Barik model. Cell volume grows exponentially, while cell cycle components such as the G1 and mitotic cyclins oscillate. Budding occurs when G1 cyclins increase through a threshold, while mitosis occurs when mitotic cyclins decrease through a threshold.
Fig 2.
Consistent pattern of parameter sensitivities across models and experimental data.
(A) Parameter sensitivities of Vdiv, Vdau, Tdiv, and TG1 across all three models under constant conditions (i.e. basal parameter values). (B) Proportions of parameters for which the sensitivities of Vdau and TG1 have the same sign (light bars) and opposite sign (dark bars). (C) Negative correlation between average volume and unbudded fraction for cells grown at constant rate under different limiting nutrients (i.e. limiting glucose (G), nitrogen (N), phosphate (P), suphur (S), leucine (L), and uracil (U)). Data from [12]. (D) Negative correlation between Vdau and TG1 for cells grown at constant rate under different nutrient and genetic perturbations. Data from [46].
Fig 3.
Example dynamic sensitivity analysis of the mitotic cyclin synthesis parameter in the Barik model (ks,bM).
(A) and
for all parameters in the Barik model, with the parameter representing mitotic cyclin synthesis marked in green. (B) Sensitivity of Vdau and TS/G2/M for four generations following a step-change in parameters applied at 30mins. (C) As in (B), for a step-change in parameters applied at 104mins. (D)
and
down generations as functions of time. Points from (B,C) are marked by blue and red circles, respectively. Vertical dashed lines represent the time of the G1-S transition.
Fig 4.
The duration of the G1 phase is particularly sensitive to changes in parameters.
(A) Comparison of sensitivities of TG1 and TS/G2/M to changes in parameters in constant conditions. The strict proportional relationship is clear in all cases. (B) Examples of monotonic changes in TG1 down generations. (C) Examples of nonmonotonic changes in TG1 down generations. (D) Comparison of fractions of parameters exhibiting monotonic and nonmonotonic changes in TG1 for all three models (see S1 Text for details of calculation).
Fig 5.
Consistent phase responses across models.
(A) Phase responses for three exemplar parameters in the Barik model. (B) Sensitivity of the fraction of cell volume donated to the daughter cell for the three parameters shown in (A). The high similarity of the functions in (A) and (B) follows from the correspondence between phase shifts and daughter cell size fraction (Eq 14). (C,D) Examples of predominantly biphasic (C) and monophasic (D) phase response curves for parameters in the Barik model. (E) Distribution of biphasic extent of parameters for all three models, evaluated according to Eq (15). (F) Distribution of peak phase sensitivities for all three models. Vertical dashed lines represent the time of the G1/S transition.
Fig 6.
Glucose signalling case study.
(A) A schematic of glucose regulation. Glucose is known to act on the cell cycle and many other processes through a diverse range of signalling pathways. We evaluate glucose modulation of the Barik model through regulation of Cln2 transcription (ks,mbS), Cln3 translation (ks,n3), and Net1 dephosphorylation (kd,t1, kd,nt). (B) The changes in behaviour mediated by increasing glucose levels are represented as vectors in the (ΔTG1, ΔVdau) space. The attainable range of behaviours is represented by the shaded region. This is consistent with experimental observations (dark blue line; see text for details). (C) The dynamic sensitivities of Vdau to the three coregulating pathways are shown. Note that the Net1 pathway is the only one that is capable of changing daughter cell size when parameters are changed late in the cell cycle (after ∼80 mins) (D) The change in daughter cell size in the first generation following an increase in glucose levels, as a function of the time of perturbation. The consequences of different balances of these three parameter perturbations are shown, all of which have the same eventual change in behaviour. The inclusion of strong regulation in mitosis (through Net1) allows dynamic response to changes in glucose levels late in the cell cycle.