In a multicellular organism, gene expression regulation allows cells to live, divide and ensure their proper physiological role. The molecular nature of this process (e.g. low molecule number, Brownian movements…) involves random variations. Indeed, with the same genetic background, two neighbor cells do not express their genes in the same way.

It is now settled that this level of stochasticity is involved in numerous biological processes (e.g. embryonic development). Recent studies have shown that during different differentiation processes, the level of stochastic gene expression (SGE) transiently increases. This rise is interpreted as the way for cells to explore a larger number of gene expression pattern’s combinations in order to increase their probability to find the right one and thus, to acquire their specific final state (e.g. red blood cell). The experimental proof of the functional inter-dependence between SGE and differentiation was lacking.

Our strategy was to artificially modulate the gene expression variability through pharmacological drugs. In this study, 3 drugs were selected to modify the level of SGE in avian erythroid progenitors. The use of single cell transcriptomic data allowed to measure the drug’s effect on SGE. Two drugs were shown to reduce the amount of SGE, whereas the third one increased it. After excluding the existence of potential side and off-target effects, we tested the influence of the 3 drugs on the ability of cells to differentiate. The results were clear: both drugs that reduced the SGE also decreased the percentage of differentiated cells. The reverse was shown with the 3rd drug: increasing SGE is accompanied by an acceleration of the differentiation dynamic. We finally used a dynamical mathematical model to confirm the specificity of these drugs on the differentiation rate in our cells.

To summarize, by using single cell transcriptomic data coupled with a mathematical model, we succeeded to experimentally demonstrate for the first time a functional link between SGE and differentiation. This study supports the theoretical assumptions on the role of SGE in differentiation and open avenues for further work on how to control this process.

Source: Drugs modulating stochastic gene expression affect the erythroid differentiation process. Anissa Guillemin, Ronan Duchesne, Fabien Crauste, Sandrine Gonin-Giraud, Olivier Gandrillon. PLOS One doi: 10.1371/journal.pone.0225166