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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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 16; p. E944 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
17.04.2012
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| ISSN: | 1091-6490, 1091-6490 |
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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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| AbstractList | 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.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. 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. |
| Author | Sweet, Matthew J Carninci, Piero Daub, Carsten O Masterman, Kelly-Anne Schroder, Kate Baillie, John Kenneth Bokil, Nilesh J Grimmond, Sean M Le Cao, Kim-Anh Suzuki, Harukazu Faulkner, Geoffrey J Gongora, Milena Hayashizaki, Yoshihide McLachlan, Geoffrey J Irvine, Katharine M Semple, Colin A Lenhard, Boris Hume, David A Kapetanovic, Ronan Goldman, Nick Akalin, Altuna Kawaji, Hideya Labzin, Larisa I Taylor, Martin S Fairbairn, Lynsey |
| Author_xml | – sequence: 1 givenname: Kate surname: Schroder fullname: Schroder, Kate email: k.schroder@imb.uq.edu.au organization: Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, Australia. k.schroder@imb.uq.edu.au – sequence: 2 givenname: Katharine M surname: Irvine fullname: Irvine, Katharine M – sequence: 3 givenname: Martin S surname: Taylor fullname: Taylor, Martin S – sequence: 4 givenname: Nilesh J surname: Bokil fullname: Bokil, Nilesh J – sequence: 5 givenname: Kim-Anh surname: Le Cao fullname: Le Cao, Kim-Anh – sequence: 6 givenname: Kelly-Anne surname: Masterman fullname: Masterman, Kelly-Anne – sequence: 7 givenname: Larisa I surname: Labzin fullname: Labzin, Larisa I – sequence: 8 givenname: Colin A surname: Semple fullname: Semple, Colin A – sequence: 9 givenname: Ronan surname: Kapetanovic fullname: Kapetanovic, Ronan – sequence: 10 givenname: Lynsey surname: Fairbairn fullname: Fairbairn, Lynsey – sequence: 11 givenname: Altuna surname: Akalin fullname: Akalin, Altuna – sequence: 12 givenname: Geoffrey J surname: Faulkner fullname: Faulkner, Geoffrey J – sequence: 13 givenname: John Kenneth surname: Baillie fullname: Baillie, John Kenneth – sequence: 14 givenname: Milena surname: Gongora fullname: Gongora, Milena – sequence: 15 givenname: Carsten O surname: Daub fullname: Daub, Carsten O – sequence: 16 givenname: Hideya surname: Kawaji fullname: Kawaji, Hideya – sequence: 17 givenname: Geoffrey J surname: McLachlan fullname: McLachlan, Geoffrey J – sequence: 18 givenname: Nick surname: Goldman fullname: Goldman, Nick – sequence: 19 givenname: Sean M surname: Grimmond fullname: Grimmond, Sean M – sequence: 20 givenname: Piero surname: Carninci fullname: Carninci, Piero – sequence: 21 givenname: Harukazu surname: Suzuki fullname: Suzuki, Harukazu – sequence: 22 givenname: Yoshihide surname: Hayashizaki fullname: Hayashizaki, Yoshihide – sequence: 23 givenname: Boris surname: Lenhard fullname: Lenhard, Boris – sequence: 24 givenname: David A surname: Hume fullname: Hume, David A – sequence: 25 givenname: Matthew J surname: Sweet fullname: Sweet, Matthew J |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22451944$$D View this record in MEDLINE/PubMed |
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| StartPage | E944 |
| SubjectTerms | 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 |
| Title | Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/22451944 https://www.proquest.com/docview/1002793418 |
| Volume | 109 |
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