What Population Reveals about Individual Cell Identity: Single-Cell Parameter Estimation of Models of Gene Expression in Yeast

Significant cell-to-cell heterogeneity is ubiquitously observed in isogenic cell populations. Consequently, parameters of models of intracellular processes, usually fitted to population-averaged data, should rather be fitted to individual cells to obtain a population of models of similar but non-identical individuals. Here, we propose a quantitative modeling framework that attributes specific parameter values to single cells for a standard model of gene expression. We combine high quality single-cell measurements of the response of yeast cells to repeated hyperosmotic shocks and state-of-the-art statistical inference approaches for mixed-effects models to infer multidimensional parameter distributions describing the population, and then derive specific parameters for individual cells. The analysis of single-cell parameters shows that single-cell identity (e.g. gene expression dynamics, cell size, growth rate, mother-daughter relationships) is, at least partially, captured by the parameter values of gene expression models (e.g. rates of transcription, translation and degradation). Our approach shows how to use the rich information contained into longitudinal single-cell data to infer parameters that can faithfully represent single-cell identity.Author Summary: Because of non-genetic variability, cells in an isogenic population respond differently to a same stimulation. Therefore, the mean behavior of a cell population does not generally correspond to the behavior of the mean cell, and more generally, neglecting cell-to-cell differences biases our quantitative representation and understanding of the functioning of cellular systems. Here we introduce a statistical inference approach allowing for the calibration of (a population of) single cell models, differing by their parameter values. It enables to view time-lapse microscopy data as many experiments performed on one cell rather than one experiment performed on many cells. By harnessing existing cell-to-cell differences, one can then learn how environmental cues affect (non-observed) intracellular processes. Our approach is generic and enables to exploit in unprecedented manner the high informative content of single-cell longitudinal data.