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Nature. 2018 Nov;563(7730):197-202. doi: 10.1038/s41586-018-0657-2. Epub 2018 Oct 24.

Gene expression variability across cells and species shapes innate immunity.

Author information

1
Wellcome Sanger Institute, Cambridge, UK. tzachi@ebi.ac.uk.
2
EMBL- European Bioinformatics Institute, Cambridge, UK. tzachi@ebi.ac.uk.
3
Wellcome Sanger Institute, Cambridge, UK.
4
Centre of Biological Engineering, University of Minho, Braga, Portugal.
5
EMBL- European Bioinformatics Institute, Cambridge, UK.
6
Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy.
7
Italian Institute for Genomic Medicine (IIGM), Torino, Italy.
8
Molecular Biotechnology Center, University of Turin, Torino, Italy.
9
Open Targets, Wellcome Sanger Institute, Cambridge, UK.
10
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
11
Division of Pathology and Microbiology, Animal Science Department, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
12
Research Department, Public Health England, National Infection Service, Porton Down, UK.
13
Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
14
Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.
15
Department of Physics, University of Washington, Seattle, WA, USA.
16
Institute for Biological Physics, University of Cologne, Cologne, Germany.
17
Wellcome Sanger Institute, Cambridge, UK. st9@sanger.ac.uk.
18
EMBL- European Bioinformatics Institute, Cambridge, UK. st9@sanger.ac.uk.
19
Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, Cambridge, UK. st9@sanger.ac.uk.

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.

PMID:
30356220
DOI:
10.1038/s41586-018-0657-2

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