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Cited by 308

The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages

Schroder, Kate, Irvine, Katharine M., Taylor, Martin S., Bokil, Nilesh J., Le Cao, Kim-Anh, Masterman, Kelly-Anne, Labzin, Larisa I., Semple, Colin A., Kapetanovic, Ronan, Fairbairn, Lynsey, Akalin, Altuna, Faulkner, Geoffrey J., Baillie, John Kenneth, Gongora, Milena, Daub, Carsten O., Kawaji, Hideya, McLachlan, Geoffrey J., Goldman, Nick, Grimmond, Sean M., Carninci, Piero, Suzuki, Harukazu, Hayashizaki, Yoshihide, Lenhard, Boris, Hume, David A., Sweet, Matthew J.·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1110156109
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Abstract

Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies differences in the transcriptional responses of primary human and mouse macrophages to the Toll-like receptor (TLR)–4 agonist lipopolysaccharide (LPS). By using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5′ ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologues were identified as “divergently regulated”). We further demonstrate concordant regulation of human-specific LPS target genes in primary pig macrophages. Divergently regulated orthologues were enriched for genes encoding cellular “inputs” such as cell surface receptors (e.g., TLR6, IL-7Rα) and functional “outputs” such as inflammatory cytokines/chemokines (e.g., CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. Functional consequences of divergent gene regulation were confirmed by showing LPS pretreatment boosts subsequent TLR6 responses in mouse but not human macrophages, in keeping with mouse-specific TLR6 induction. Divergently regulated genes were associated with a large dynamic range of gene expression, and specific promoter architectural features (TATA box enrichment, CpG island depletion). Surprisingly, regulatory divergence was also associated with enhanced interspecies promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change.

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Research works printed but not linked: 2

  1. J Mestas, CC Hughes, Of mice and not men: Differences between mouse and human immunology. J Immunol 172, 2731–2738 (2004). · DOI · Paper page
  2. N Maeda, et al., Development of a DNA barcode tagging method for monitoring dynamic changes in gene expression by using an ultra high-throughput sequencer. Biotechniques 45, 95–97 (2008). · DOI

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Authors
Schroder, K., Irvine, K. M., Taylor, M. S., Bokil, N. J., Le Cao, K.-A., Masterman, K.-A., Labzin, L. I., Semple, C. A., Kapetanovic, R., Fairbairn, L., Akalin, A., Faulkner, G. J., Baillie, J. K., Gongora, M., Daub, C. O., Kawaji, H., McLachlan, G. J., Goldman, N., Grimmond, S. M., Carninci, P., Suzuki, H., Hayashizaki, Y., Lenhard, B., Hume, D. A., & Sweet, M. J.
Affiliations
  • Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia;
  • European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, United Kingdom;
  • Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;
  • Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, United Kingdom;
  • Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY 10065;
  • RIKEN Omics Science Center, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan;
  • Medical Research Council Clinical Sciences Centre, Institute of Clinical Sciences, Imperial College London, London W12 0NN, United Kingdom
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-03-26
Volume
109
Issue
16
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1110156109
Cited by
308
References
54
Language
en

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