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

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. and Sweet, Matthew J. (2012) Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proceedings of the National Academy of Sciences of the USA, 109 16: E944-E953. doi:10.1073/pnas.1110156109


Author 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.
Title Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages
Journal name Proceedings of the National Academy of Sciences of the USA   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2012-04-17
Sub-type Article (original research)
DOI 10.1073/pnas.1110156109
Open Access Status Not Open Access
Volume 109
Issue 16
Start page E944
End page E953
Total pages 10
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Collection year 2013
Language eng
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.
Keyword Evolution
Inflammation
Innate immunity
Pattern-recognition receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 29 Mar 2012, 16:19:41 EST by Dr Kate Schroder on behalf of Institute for Molecular Bioscience