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Gene-specific linear trends constrain transcriptional variability of the toll-like receptor signaling
Bagnall, J. Rowe, W. Alachkar, N. Roberts, J. England, H. Clark, Christopher Platt, M. Jackson, D. A. Muldoon, M. Paszek, P.
Bagnall, J.
Rowe, W.
Alachkar, N.
Roberts, J.
England, H.
Clark, Christopher
Platt, M.
Jackson, D. A.
Muldoon, M.
Paszek, P.
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Abstract
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.
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Date
2020
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Bagnall J, Rowe W, Alachkar N, Roberts J, England H, Clark C, et al. Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling. Cell Syst. 2020;11(3):300-14 e8.