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

Area of Science:

• Developmental Biology
• Cellular Biology
• Evolutionary Biology

Background:

• Isogenic cells can differentiate into distinct cell types despite uniform environments, a conserved mechanism crucial for unicellular survival and multicellular evolution.
• Cell-cell variation is hypothesized to prime cells for different lineages, but the precise molecular mechanisms remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms underlying probabilistic cell differentiation and lineage choice in isogenic cells.
• To develop and validate a model explaining single-cell quantitative observations of cell fate determination.

Main Methods:

• Utilized the social amoeba *Dictyostelium discoideum* as a model system for studying cell fate without spatial cues.
• Developed and tested a quantitative model for probabilistic differentiation.
• Performed single-cell sequencing to analyze gene expression variation.

Main Results:

• The model indicated that both cell cycle position and stochastic cell-cell variation significantly influence lineage choice.
• Single-cell sequencing identified genes with stochastic expression patterns that are critical for cell fate determination.
• Genes affecting cell fate were found to be associated with H3K4 methylation, and its perturbation disrupted lineage choice.

Conclusions:

• Stochastic cell-cell variation plays a critical role in cell fate decisions, complementing deterministic signals like cell cycle position.
• The integration of stochastic and deterministic factors enhances developmental robustness against environmental perturbations.
• This study provides insights into the fundamental mechanisms driving cell differentiation and the evolution of complexity.