Integration of RNA-seq transcriptomics with metabolomics in mouse model of cigarette smoke exposure

Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality, is primarily caused by prolonged exposures to cigarette smoke (CS) and the disease may persist or progress even after smoking cessation. To provide novel insight the mechanisms of COPD development we investigated temporal patterns of lung transcriptome expression in response to chronic CS exposure that also persist following CS cessation, using next generation sequencing techniques. Whole lung RNA-seq data was analyzed from C57Bl/6 mice exposed to CS for 1 day, 7 days, 1 month, 3 months, 6 months, and 9 months as well as for 6 months followed by 3 months of cessation. Age-matched littermate mice exposed to ambient air were used as control (AC). Differential gene expression and pathway analyses revealed consistent upregulation of genes involved in glutathione metabolism, a pathway previously implicated in lung responses to chronic CS and in COPD, that was reversible upon cessation. In addition, novel patterns in mouse-model pathways such as pyrimidine metabolism and phosphatidylinositol signaling system and have been recognized. Genes in these pathways encoding for enzymes controlling metabolic functions were significantly altered by CS exposures and were associated with congruent abnormalities in contemporaneous plasma metabolomic profiles. The bioinformatics integration of lung tissue genomics and plasma metabolomics uncovered that changes in lung gene expression induced by CS exposures are translated in systemic metabolic signatures, with potential implication in the development of COPD. Overall design: Whole transcriptome profiling of air control vs cigarette smoke-exposed mice at each of 6 timepoints from 1 day to 9 months of exposure, including a stop smoking group exposed to 6 months of CS followed by 3 months of ambient air recovery. Each treatment-by-time experimental group contains 5 biological replicates. 3 samples were discarded for quality reasons.

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Miller MA, Danhorn T, Cruickshank-Quinn CI, Leach SM, Jacobson S, Strand MJ, Reisdorph NA, Bowler RP, Petrache I, Kechris K