Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 16, Pages E944-E953Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110156109
Keywords
evolution; inflammation; innate immunity; pattern-recognition receptor; transcriptional regulation
Categories
Funding
- Australian National Health and Medical Research Council [490993, APP1003470]
- Australian Research Council under the ARC Centres of Excellence (ARC Centre of Excellence in Bioinformatics)
- Australian Research Council [FT100100657]
- Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)
- Biotechnology and Biological Sciences Research Council [BB/I024801/1, BBS/E/D/20241864, BBS/E/D/20241863, BBS/E/D/20241866, BBS/E/D/20251969] Funding Source: researchfish
- Medical Research Council [MC_PC_U127597124, MC_U127597124] Funding Source: researchfish
- Australian Research Council [FT100100657] Funding Source: Australian Research Council
- BBSRC [BBS/E/D/20241866, BBS/E/D/20241863, BB/I024801/1, BBS/E/D/20251969, BBS/E/D/20241864] Funding Source: UKRI
- MRC [MC_U127597124, MC_PC_U127597124] Funding Source: UKRI
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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-7R alpha) 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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