title: Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
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.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia. k.schroder@imb.uq.edu.au
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Irvine
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Bokil
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Le Cao
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Masterman
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Labzin
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
authors.forename: Ronan
authors.initials: R
authors.lastname: Kapetanovic
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fairbairn
authors.forename: Altuna
authors.initials: A
authors.lastname: Akalin
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
authors.forename: John Kenneth
authors.initials: JK
authors.lastname: Baillie
authors.forename: Milena
authors.initials: M
authors.lastname: Gongora
authors.forename: Carsten O
authors.initials: CO
authors.lastname: Daub
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: McLachlan
authors.forename: Nick
authors.initials: N
authors.lastname: Goldman
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics; D054382:Chemokine CXCL13 / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000502:physiology; D013045:Species Specificity; D013552:Swine; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics*
chemical_list: D054418:Chemokine CCL20; D054382:Chemokine CXCL13; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4