Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptional responses of human monocyte-derived macrophages (HMDM) to lipopolysaccharide (LPS)

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 inter-species differences in the transcriptional responses of primary human and mouse macrophages to the TLR4 agonist, LPS. Using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5M-bM-^@M-^Y ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologs, http://www.macgate.qfab.org). Divergently regulated (DR) orthologs were enriched for genes encoding cellular M-bM-^@M-^\inputsM-bM-^@M-^] such as cell surface receptors (e.g. TLR6, IL-7RM-NM-1), and functional M-bM-^@M-^\outputsM-bM-^@M-^] such as inflammatory cytokines/chemokines (e.g. CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. DR 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 inter-species promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change. Human monocyte-derived macrophages (HMDM) were stimulated with the TLR4 agonist, lipopolysaccharide, over a time course (0, 2, 6, 24h) and analysed in biological quadruplicate (each of which represents a pool of two independent blood donors), in total representing 8 macrophage preparations from independent blood donors, on a custom-designed, focused microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Kate Schroder

PROVIDER: E-GEOD-19482 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Schroder Kate K Irvine Katharine M KM Taylor Martin S MS Bokil Nilesh J NJ Le Cao Kim-Anh KA Masterman Kelly-Anne KA Labzin Larisa I LI Semple Colin A CA Kapetanovic Ronan R Fairbairn Lynsey L Akalin Altuna A Faulkner Geoffrey J GJ Baillie John Kenneth JK Gongora Milena M Daub Carsten O CO Kawaji Hideya H McLachlan Geoffrey J GJ Goldman Nick N Grimmond Sean M SM Carninci Piero P Suzuki Harukazu H Hayashizaki Yoshihide Y Lenhard Boris B Hume David A DA Sweet Matthew J MJ

Proceedings of the National Academy of Sciences of the United States of America 20120326 16

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 ...[more]

PMID: 22451944

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Project description:A comprehensive in vitro assessment of two commercial metal oxide nanoparticles, TiO2 and ZnO, was performed using human monocyte-derived macrophages (HMDM), monocyte-derived dendritic cells (MDDC), and T cell leukemia-derived cell line (Jurkat). TiO2 nanoparticles were found to be non-toxic whereas ZnO nanoparticles caused dose-dependent cell death. Subsequently, global gene expression profiling was performed to identify signaling pathways underlying the cytotoxicity caused by ZnO nanoparticles. Analysis was done with doses, 1M-BM-5g/ml and 10M-BM-5g/ml after 6 and 24 hours of exposure. Interestingly, 2703 genes were significantly differentially expressed in HMDM upon exposure to 10M-BM-5g/ml ZnO nanoparticles, while in MDDCs only 12 genes were affected. In Jurkat cells, 980 genes were differentially expressed. It is noteworthy that the gene expression of metallothioneins was upregulated in all the three cell types. In addition to the common ZnO-inducible changes, a notable proportion of the genes were regulated in a cell type-specific manner. Using a panel of ZnO nanoparticles, we obtained an additional support that the cellular response to ZnO nanoparticles is caused by particle dissolution. Gene ontology analysis revealed that the top biological processes disturbed in HMDM and Jurkat cells were regulating cell death and growth. In addition, genes controlling immune system development were affected. Bioinformatics assessment showed that the top human disease category associated with ZnO-responsive genes in both HMDM and Jurkat cells was cancer. Overall, the study revealed novel genes and pathways for mediating ZnO nanoparticle-induced toxicity and demonstrated the value of assessing nanoparticle responses through combined transcriptomics and bioinformatics approach. Altogether 90 samples were analyzed originating from three biological replicates of HMDM, MDDC or Jurkat cells containg untreated control cells, ZnO or TiO2 treated cells with doses 1M-BM-5g/ml and 10M-BM-5g/ml. The sample timepoints were 6 hours and 24 hours.

Dataset Information

Transcriptional responses of human monocyte-derived macrophages (HMDM) to lipopolysaccharide (LPS)

Publications

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

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