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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 16; pp. 5925 - 5926
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.04.2012; National Acad Sciences
• Series: PNAS Plus
• Subjects: agonists; Animals; Biological Sciences; Cell Line; Cells, Cultured; Chemokine CCL20; Chemokine CCL20 - genetics; Chemokine CXCL13; Chemokine CXCL13 - genetics; chemokines; drug effects; Evolution; Evolution, Molecular; Female; Gene expression; Gene Expression Profiling; gene expression regulation; Gene Expression Regulation - drug effects; genes; Genetic Variation; genetics; genomic islands; high-throughput nucleotide sequencing; Host-Pathogen Interactions; Human subjects; Humans; Immunology; Leukocytes; Life Sciences; lipopolysaccharides; Lipopolysaccharides - pharmacology; macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - microbiology; Male; messenger RNA; metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; microbiology; Microbiology and Parasitology; Oligonucleotide Array Sequence Analysis; pharmacology; physiology; PNAS Plus; PNAS PLUS (AUTHOR SUMMARIES); receptors; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Salmonella typhimurium; Salmonella typhimurium - physiology; Signal transduction; Species Specificity; Swine; TATA box; Toll-Like Receptor 4; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - genetics; Innate immunity; Inflammation; evolution; Transcriptional regulation; Pattern-recognition receptor
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1110156109

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.