Linage priming and cell type proportioning depends on the interplay between stochastic and deterministic factors

Joint Public Review:

Summary:

The authors investigate how stochastic and deterministic factors are integrated in cell fate decisions, using Dictyostelium discoideum as a model system. They show that cells in different cell cycle phases (a deterministic factor) are predisposed to different fates, albeit with deviations, when exposed to the same environmental stimulus. However, gene expression variability (a stochastic factor) enhances the robustness of cellular responses to environmental cues that disrupt the cell cycle.

Using a simple, tractable mathematical model, the authors demonstrate that cell fate decisions in D. discoideum depend on a combination of deterministic and stochastic factors, i.e., cell cycle phase and gene expression variability, respectively. They then identify Set1 - a key regulator of gene expression variability - indicate the mechanism through which it modulates this variability, and link it to a phenotype in D. discoideum development. Finally, they confirm that gene expression variability contributes to the robustness of the cell's response to environmental disruptions that interfere with the cell cycle.

Strengths:

The authors are careful in the choice of their experiments and in measuring gene expression variability, using methods that account for expected trends with average gene expression.

Weaknesses:

However, in terms of mathematical modelling, it would be important to rule out sources of stochasticity (other than gene expression variability), and also to consider cases where stochastic factors are not necessarily completely independent of the deterministic ones.