A central question in biology is whether variability between genetically identical cells exposed to the same culture conditions is largely stochastic or deterministic. Using image-based transcriptomics in millions of single human cells, we find that while variability of cytoplasmic transcript abundance is large, it is for most genes minimally stochastic and can be predicted with multivariate models of the phenotypic state and population context of single cells. Computational multiplexing of these predictive signatures across hundreds of genes revealed a complex regulatory system that controls the observed variability of transcript abundance between individual cells. Mathematical modeling and experimental validation show that nuclear retention and transport of transcripts between the nucleus and the cytoplasm is central to buffering stochastic transcriptional fluctuations in mammalian gene expression. Our work indicates that cellular compartmentalization confines transcriptional noise to the nucleus, thereby preventing it from interfering with the control of single-cell transcript abundance in the cytoplasm.
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