Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

摘要

The small airway epithelium (SAE), the first site of smoking-induced lung pathology, exhibits genome-wide changes in geneexpression in response to cigarettesmoking.Basedonthe increasing evidence that the epigenome can respond to external stimuli in a rapid manner, we assessed the SAE of smokers for genome-wide DNA methylation changes compared with nonsmokers, and whether changes inSAEDNAmethylation were linked to the transcriptional output of these cells. Using genome-wide methylation analysis of SAE DNA of nonsmokers and smokers, the data identified 204 unique genes differentially methylated in SAE DNA of smokers compared withnonsmokers, with67%of the regions with differentialmethylation occurring within 2 kbof the transcriptional start site. Among the genes with differential methylation were those related to metabolism, transcription, signal transduction and transport. For the differentially methylated genes, 35 exhibited a correlation with gene expression, 54% with an inverse correlation of DNA methylation with gene expression and 46% a direct correlation. These observations provide evidence that cigarette smoking alters the DNA methylation patterning of the SAE and that, for some genes, these changes are associated with the smoking-related changes in gene expression.