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Bagnall J.♦, Rowe W.♦, Alachkar N.♦, Roberts J.♦, England H.♦, Clark C.♦, Platt M.♦, Jackson Dean A.♦, Muldoon M.♦, Paszek P.♦, Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling,
Cell Systems, ISSN: 2405-4712, DOI: 10.1016/j.cels.2020.08.007, Vol.11, No.3, pp.300-314, 2020Abstract: Single-cell gene expression is inherently variable, but how this variability is controlled in response to stimulation remains unclear. Here, we use single-cell RNA-seq and single-molecule mRNA counting (smFISH) to study inducible gene expression in the immune toll-like receptor system. We show that mRNA counts of tumor necrosis factor α conform to a standard stochastic switch model, while transcription of interleukin-1β involves an additional regulatory step resulting in increased heterogeneity. Despite different modes of regulation, systematic analysis of single-cell data for a range of genes demonstrates that the variability in transcript count is linearly constrained by the mean response over a range of conditions. Mathematical modeling of smFISH counts and experimental perturbation of chromatin state demonstrates that linear constraints emerge through modulation of transcriptional bursting along with gene-specific relationships. Overall, our analyses demonstrate that the variability of the inducible single-cell mRNA response is constrained by transcriptional bursting. Keywords: cellular heterogeneity, transcriptional bursting, stochastic gene expression, toll-like receptor, single-cell transcriptomics, stochastic modeling, TNF-α, IL-1β Affiliations:
Bagnall J. | - | other affiliation | Rowe W. | - | other affiliation | Alachkar N. | - | other affiliation | Roberts J. | - | other affiliation | England H. | - | other affiliation | Clark C. | - | other affiliation | Platt M. | - | other affiliation | Jackson Dean A. | - | other affiliation | Muldoon M. | - | other affiliation | Paszek P. | - | other affiliation |
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