Gene expression variability across cells and species shapes innate immunity

Tzachi Hagai*, Xi Chen, Ricardo J. Miragaia, Raghd Rostom, Tomás Gomes, Natalia Kunowska, Johan Henriksson, Jong Eun Park, Valentina Proserpio, Giacomo Donati, Lara Bossini-Castillo, Felipe A. Vieira Braga, Guy Naamati, James Fletcher, Emily Stephenson, Peter Vegh, Gosia Trynka, Ivanela Kondova, Mike Dennis, Muzlifah HaniffaArmita Nourmohammad, Michael Lässig, Sarah A. Teichmann

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

As the first line of defence against pathogens, cells mount an innate immune response, which varies widely from cell to cell. The response must be potent but carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here we characterize the innate immune response’s transcriptional divergence between species and variability in expression among cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we map the architecture of the innate immune response. Transcriptionally diverging genes, including those that encode cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes that are involved in the regulation of this response, such as those that encode transcription factors and kinases, are conserved between species and display low cell-to-cell variability in expression. We suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective but balanced response.

Original languageEnglish
Pages (from-to)197-202
Number of pages6
JournalNature
Volume563
Issue number7730
DOIs
StatePublished - 8 Nov 2018
Externally publishedYes

Funding

FundersFunder number
EMBO Long-Term and Advanced fellowships
Wellcome SangerWT206194
Human Frontier Science Program
Horizon 2020 Framework Programme260507, 646794, 664918
Seventh Framework Programme
European Commission
European Research Council
Fondazione Umberto Veronesi

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