Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages
Year: 2012
Type: article
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: Kate Schroder, Katharine M. Irvine, Martin S. Taylor, Nilesh J. Bokil, Kim-Anh Le Cao, Kelly-Anne Masterman, Larisa I. Labzin, Colin A. Semple, Ronan Kapetanovic, Lynsey Fairbairn, Altuna Akalin, Geoffrey J. Faulkner, John Kenneth Baillie, Milena Gongora, Carsten O. Daub, Hideya Kawaji, Geoffrey J. McLachlan, Nick Goldman, Sean M. Grimmond, Piero Carninci, Harukazu Suzuki, Yoshihide Hayashizaki, Boris Lenhard, David A. Hume, Matthew J. Sweet
Institutions: The University of Queensland, Institute for Molecular Bioscience, European Bioinformatics Institute, Western General Hospital, MRC Human Genetics Unit, Wellcome Trust, Roslin Institute, University of Edinburgh, Cornell University, Weill Cornell Medicine, RIKEN, RIKEN Center for Integrative Medical Sciences, Imperial College London, Medical Research Council
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Novel strategies to control virus infection and disease, Identifying mechanisms regulating central nervous system homeostasis, Mechanistic understanding of virus pathogenesis and resistance, Host genetic resistance to viruses, A complete transcriptional map of the human body: systems biology in toto, G8475430463
OpenAlex ID: W1997423398