Gene-specific linear trends constrain transcriptional variability of the toll-like receptor signalling

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • William Rowe
  • Nissrin Alachkar
  • James Roberts
  • Christopher Clark
  • Mark Platt

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1-15
JournalCell Systems
Volume11
Issue number3
DOIs
Publication statusPublished - 11 Sep 2020

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