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GSE69770: Tobacco smoke-inducible enhancers linked to xenobiotic response genes and lung carcinogenesis identified through analysis of lung tissue epigenomes

Bulk RNA sequencing

Smoking-associated DNA hypomethylation has been observed in blood cells and was recently linked to lung cancer risk. However, its cause and mechanistic relationship to lung cancer remain unclear. We studied the association between tobacco smoking and epigenome-wide methylation in non-tumor lung tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, with replication in The Cancer Genome Atlas. We identified seven smoking-associated hypomethylated CpGs (P = 1.0x10-7); four CpGs border sequences carrying aryl hydrocarbon receptor binding sites and enhancer-specific histone modifications in primary alveolar epithelium and A549 lung adenocarcinoma cells. A549 cell exposure to cigarette smoke condensate increased these enhancer marks and stimulated expression of predicted target xenobiotic response-related genes AHRR (P = 1.13x10-62) and CYP1B1 (P = 2.49x10-61). Expression of both genes was linked to smoking-related transversion mutations in lung tumors. Thus, smoking-associated hypomethylation may be a consequence of enhancer activation, revealing environmentally-induced regulatory elements implicated in lung carcinogenesis. SOURCE: Crystal,N,Marconett (cmarcone@usc.edu) - Crystal Marconett University of Southern California

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