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

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...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 109; H. 16; S. E944
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: United States 17.04.2012
Schlagworte:
Animals
Cell Line
Cells, Cultured
Chemokine CCL20 - genetics
Chemokine CXCL13 - genetics
Evolution, Molecular
Female
Gene Expression Profiling
Gene Expression Regulation - drug effects
Genetic Variation
Host-Pathogen Interactions
Humans
Lipopolysaccharides - pharmacology
Macrophages - drug effects
Macrophages - metabolism
Macrophages - microbiology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Salmonella typhimurium - physiology
Species Specificity
Swine
Toll-Like Receptor 4 - agonists
Toll-Like Receptor 4 - genetics
ISSN:1091-6490, 1091-6490
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1110156109