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

Schroder, K; Irvine, KM; Taylor, MS; Bokil, NJ; Le Cao, KA; Masterman, KA; Labzin, LI; Semple, CA; Kapetanovic, R; Fairbairn, L; Akalin, A; Faulkner, GJ; Baillie, JK; Gongora, M; Daub, CO; Kawaji, H; McLachlan, GJ; Goldman, N; Grimmond, SM; Carninci, P; Suzuki, H; Hayashizaki, Y; Lenhard, B; Hume, DA; Sweet, MJ

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

Schroder, K Irvine, KM Taylor, MS Bokil, NJ

Le Cao, KA Masterman, KA Labzin, LI Semple, CA Kapetanovic, R Fairbairn, L Akalin, A Faulkner, GJ Baillie, JK Gongora, M Daub, CO Kawaji, H McLachlan, GJ Goldman, N Grimmond, SM Carninci, P Suzuki, H Hayashizaki, Y Lenhard, B Hume, DA Sweet, MJ

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Publication Type:: Journal Article
Citation:: Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (16)
Issue Date:: 2012-04-17

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Field	Value	Language
dc.contributor.author	Schroder, K	en_US
dc.contributor.author	Irvine, KM	en_US
dc.contributor.author	Taylor, MS	en_US
dc.contributor.author	Bokil, NJ https://orcid.org/0000-0003-3202-9249	en_US
dc.contributor.author	Le Cao, KA	en_US
dc.contributor.author	Masterman, KA	en_US
dc.contributor.author	Labzin, LI	en_US
dc.contributor.author	Semple, CA	en_US
dc.contributor.author	Kapetanovic, R	en_US
dc.contributor.author	Fairbairn, L	en_US
dc.contributor.author	Akalin, A	en_US
dc.contributor.author	Faulkner, GJ	en_US
dc.contributor.author	Baillie, JK	en_US
dc.contributor.author	Gongora, M	en_US
dc.contributor.author	Daub, CO	en_US
dc.contributor.author	Kawaji, H	en_US
dc.contributor.author	McLachlan, GJ	en_US
dc.contributor.author	Goldman, N	en_US
dc.contributor.author	Grimmond, SM	en_US
dc.contributor.author	Carninci, P	en_US
dc.contributor.author	Suzuki, H	en_US
dc.contributor.author	Hayashizaki, Y	en_US
dc.contributor.author	Lenhard, B	en_US
dc.contributor.author	Hume, DA	en_US
dc.contributor.author	Sweet, MJ	en_US
dc.date.issued	2012-04-17	en_US
dc.identifier.citation	Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (16)	en_US
dc.identifier.issn	0027-8424	en_US
dc.identifier.uri	http://hdl.handle.net/10453/115115
dc.description.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 crossspecies 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.	en_US
dc.relation.ispartof	Proceedings of the National Academy of Sciences of the United States of America	en_US
dc.relation.isbasedon	10.1073/pnas.1110156109	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Cell Line	en_US
dc.subject.mesh	Macrophages	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred BALB C	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Swine	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Salmonella typhimurium	en_US
dc.subject.mesh	Lipopolysaccharides	en_US
dc.subject.mesh	Oligonucleotide Array Sequence Analysis	en_US
dc.subject.mesh	Gene Expression Profiling	en_US
dc.subject.mesh	Reverse Transcriptase Polymerase Chain Reaction	en_US
dc.subject.mesh	Evolution, Molecular	en_US
dc.subject.mesh	Species Specificity	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Toll-Like Receptor 4	en_US
dc.subject.mesh	Chemokine CXCL13	en_US
dc.subject.mesh	Chemokine CCL20	en_US
dc.subject.mesh	Host-Pathogen Interactions	en_US
dc.subject.mesh	Genetic Variation	en_US
dc.title	Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages	en_US
dc.type	Journal Article
utslib.citation.volume	16	en_US
utslib.citation.volume	109	en_US
utslib.for	0604 Genetics	en_US
utslib.for	1107 Immunology	en_US
utslib.for	110303 Clinical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	16	en_US
pubs.publication-status	Published	en_US
pubs.volume	109	en_US

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 crossspecies 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/115115