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

Kate Schroder, Katharine M Irvine, Martin S Taylor, Nilesh J Bokil, Kim-Anh Le Cao, Kelly-Anne Masterman, Larisa I Labzin, Colin A Semple, Ronan Kapetanovic, Lynsey Fairbairn, Altuna Akalin, Geoffrey J Faulkner, John Kenneth Baillie, Milena Gongora, Carsten O Daub, Hideya Kawaji, Geoffrey J McLachlan, Nick Goldman, Sean M Grimmond, Piero CarninciHarukazu Suzuki, Yoshihide Hayashizaki, Boris Lenhard, David A Hume, Matthew J Sweet

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)E944-E953
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number16
Early online date28 Mar 2012
Publication statusPublished - 17 Apr 2012

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Cell Line
  • Cells, Cultured
  • Chemokine CCL20
  • Chemokine CXCL13
  • Evolution, Molecular
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Variation
  • Host-Pathogen Interactions
  • Humans
  • Lipopolysaccharides
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Salmonella typhimurium
  • Species Specificity
  • Swine
  • Toll-Like Receptor 4


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