Linage priming and cell type proportioning depends on the interplay between stochastic and deterministic factors
Curation statements for this article:-
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eLife Assessment
This valuable study investigates how stochastic and deterministic factors are integrated during cellular decision-making, particularly in situations where cells differentiate into distinct fates despite being exposed to the same environmental conditions. The authors present convincing evidence that gene expression variability contributes to the robustness of cell fate decisions in D. discoideum, which sheds light into the role of stochasticity during cell differentiation.
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Abstract
Abstract
Embryonic stem cells (ESCs) can break symmetry and differentiate along different lineages, even when exposed to a seemingly identical environment. It is thought that this priming of cells towards different lineages is due to cell-cell variation, although the underlying mechanisms are poorly understood. To address this, we exploit the tractability of the social amoeba Dictyostelium discoideum, where cell fate choice also does not depend on spatial cues. We develop and test a model to explain quantitative experimental single cell observations of probabilistic differentiation. The model suggests that cell cycle position affects lineage choice, as previously shown, but that stochastic cell-cell variation also plays a key role. Single cell sequencing reveals genes strongly associated with fate choice exhibit extensive stochastic cell-cell expression variation. Like lineage priming genes in ESCs, they are associated with specific epigenetic modifications, which when perturbed affect their expression and disrupt fate choice. We suggest this represents an adaptive mechanism that increases developmental robustness against perturbations that affect deterministic signals.
Article activity feed
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eLife Assessment
This valuable study investigates how stochastic and deterministic factors are integrated during cellular decision-making, particularly in situations where cells differentiate into distinct fates despite being exposed to the same environmental conditions. The authors present convincing evidence that gene expression variability contributes to the robustness of cell fate decisions in D. discoideum, which sheds light into the role of stochasticity during cell differentiation.
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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 - …
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.
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