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

Item Type:Article
Title:Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages
Creators Name:Schroder, K. and Irvine, K.M. and Taylor, M.S. and Bokil, N.J. and Le Cao, K.A. and Masterman, K.A. and Labzin, L.I. and Semple, C.A. and Kapetanovic, R. and Fairbairn, L. and Akalin, A. and Faulkner, G.J. and Baillie, J.K. and Gongora, M. and Daub, C.O. and Kawaji, H. and McLachlan, G.J. and Goldman, N. and Grimmond, S.M. and Carninci, P. and Suzuki, H. and Hayashizaki, Y. and Lenhard, B. and Hume, D.A. and Sweet, M.J.
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-7Ralpha) 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.
Keywords:Evolution, Inflammation, Innate Immunity, Pattern-Recognition Receptor, Transcriptional Regulation, Animals, Mice, Swine
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:109
Number:16
Page Range:E944-E953
Date:17 April 2012
Official Publication:https://doi.org/10.1073/pnas.1110156109
PubMed:View item in PubMed

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