A cell-based probabilistic approach unveils the concerted action of miRNAs

Abstract

Mature microRNAs (miRNAs) regulate most human genes through direct base-pairing with mRNAs. We investigate some underlying principles of such regulation. To this end, we overexpressed miRNAs in different cell types and measured the mRNA decay rate under transcriptional arrest. Parameters extracted from these experiments were incorporated into a computational stochastic framework which was developed to simulate the cooperative action of miRNAs in living cells. We identified gene sets that exhibit coordinated behavior with respect to all major miRNAs, over a broad range of overexpression levels. While a small set of genes is highly sensitive to miRNA manipulations, about 180 genes are insensitive to miRNA manipulations as measured by their degree of mRNA retention. The insensitive genes are associated with the translation machinery. We conclude that the stochastic nature of miRNAs reveals an unexpected robustness of gene expression in living cells. Moreover, the use of a systematic probabilistic approach exposes design principles of cells states and in particular, the translational machinery.\n\nHighlightsO_LIA probabilistic-based simulator assesses the cellular response to thousands of miRNA overexpression manipulations\nC_LIO_LIThe translational machinery displays an exceptional resistance to manipulations of miRNAs.\nC_LIO_LIThe insensitivity of the translation machinery to miRNA manipulations is shared by different cell types\nC_LIO_LIThe composition of the most abundant miRNAs dominates cell identity\nC_LI