Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers
Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers
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DOI：
10.1093/hmg/ddx188
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Landi，Maria Teresa
中科院分区：
文献类型：
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作者：
Stueve，Theresa Ryan;Li，Wen-Qing;Landi，Maria Teresa
在血细胞中观察到与吸烟相关的 DNA 低甲基化，并与肺癌风险相关。然而，其与肺癌的病因和机制关系仍不清楚。我们使用 Infinium HumanMmethylation450 BeadChip，研究了吸烟与肺癌病因学环境与遗传学研究中 237 例肺癌病例的非肿瘤肺 (NTL) 组织中表观基因组甲基化之间的关联。我们确定了 7 个与吸烟相关的低甲基化 CpG（P< 1.0 × 10−7），这些 CpG 在癌症基因组图谱的 NTL 数据中得到了重复。其中五个位点先前被报道在吸烟者的血液中甲基化程度较低，这表明基于血液的生物标志物可以反映这些位点的靶组织的变化。原代肺泡上皮和 A549 肺腺癌细胞中的四个 CpG 边界序列携带芳烃受体结合位点和增强子特异性组蛋白修饰。 A549细胞暴露于香烟烟雾冷凝物中显着增加了这些增强子标记，并刺激了预测的目标外源性反应相关基因AHRR（P =1.13 × 10−62）和CYP1B1（P< 2.49 × 10−61）的表达。这两个基因的表达与肺部肿瘤中吸烟相关的颠换突变有关。因此，与吸烟相关的低甲基化可能是增强子激活的结果，揭示了与肺癌发生有关的环境诱导的调节元件。
Smoking-associated DNA hypomethylation has been observed in blood cells and 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 (NTL) tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, using the Infinium HumanMethylation450 BeadChip. We identified seven smoking-associated hypomethylated CpGs (P< 1.0 × 10−7), which were replicated in NTL data from The Cancer Genome Atlas. Five of these loci were previously reported as hypomethylated in smokers’ blood, suggesting that blood-based biomarkers can reflect changes in the target tissue for these loci. 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 significantly and stimulated expression of predicted target xenobiotic response-related genesAHRR(P =1.13 × 10−62) andCYP1B1(P< 2.49 × 10−61).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.