Gene expression variability across cells and species shapes innate immunity.
Tzachi Hagai, Xi Chen, Ricardo J Miragaia, Raghd Rostom, Tom��s 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 Haniffa, Armita Nourmohammad, Michael L��ssig, Sarah A Teichmann
Author Information
Tzachi Hagai: Wellcome Sanger Institute, Cambridge, UK. tzachi@ebi.ac.uk.
Xi Chen: Wellcome Sanger Institute, Cambridge, UK.
Ricardo J Miragaia: Wellcome Sanger Institute, Cambridge, UK.
Raghd Rostom: Wellcome Sanger Institute, Cambridge, UK.
Tom��s Gomes: Wellcome Sanger Institute, Cambridge, UK.
Natalia Kunowska: Wellcome Sanger Institute, Cambridge, UK.
Johan Henriksson: Wellcome Sanger Institute, Cambridge, UK.
Jong-Eun Park: Wellcome Sanger Institute, Cambridge, UK.
Valentina Proserpio: Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy.
Giacomo Donati: Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy.
Lara Bossini-Castillo: Wellcome Sanger Institute, Cambridge, UK.
Felipe A Vieira Braga: Wellcome Sanger Institute, Cambridge, UK.
Guy Naamati: EMBL- European Bioinformatics Institute, Cambridge, UK.
James Fletcher: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Emily Stephenson: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Peter Vegh: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Gosia Trynka: Wellcome Sanger Institute, Cambridge, UK.
Ivanela Kondova: Division of Pathology and Microbiology, Animal Science Department, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Mike Dennis: Research Department, Public Health England, National Infection Service, Porton Down, UK.
Muzlifah Haniffa: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Armita Nourmohammad: Max Planck Institute for Dynamics and Self-Organization, G��ttingen, Germany.
Michael L��ssig: Institute for Biological Physics, University of Cologne, Cologne, Germany.
Sarah A Teichmann: Wellcome Sanger Institute, Cambridge, UK. st9@sanger.ac.uk.
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.
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