Drugs modulating stochastic gene expression affect the erythroid differentiation process

Background To understand how a metazoan cell makes the decision to differentiate, we assessed the role of stochastic gene expression (SGE) during the erythroid differentiation process. Our hypothesis is that stochastic gene expression has a role in single-cell decision-making. In agreement with this hypothesis, we and others recently showed that SGE significantly increased during differentiation. However, evidence for the causative role of SGE is still lacking. Such demonstration would require being able to experimentally manipulate SGE levels and analyze the resulting impact of these variations on cell differentiation. Result We identified three drugs that modulate SGE in primary erythroid progenitor cells. Artemisinin and Indomethacin simultaneously decreased SGE and reduced the amount of differentiated cells. Inversely, α-methylene-γ-butyrolactone-3 (MB-3) simultaneously increased the level of SGE and the amount of differentiated cells. We then used a dynamical modelling approach which confirmed that differentiation rates were indeed affected by the drug treatment. Conclusion Using single-cell analysis and modeling tools, we provide experimental evidence that in a physiologically relevant cellular system, control of SGE can directly modify differentiation, supporting a causal link between the two.