Abstract

To explore the epigenetic alterations in response to DNA damage following polycyclic aromatic hydrocarbons (PAHs) exposure and the crosstalk between different epigenetic regulations, we examined trimethylated Lys 36 of histone H3 (H3K36me3) and methylation of ‘long interspersed element-1 (LINE-1)’ and ‘O ⁶-methylguanine-DNA methyltransferase (MGMT)’ in peripheral blood lymphocytes (PBLCs) of 173 coke oven workers (PAH-exposed group) and 94 non-exposed workers (control group). The PAH-exposed group showed higher internal PAH exposure level, enhanced DNA damage and increased MGMT expression (all P < 0.001). Notably, the methylation of LINE-1 and MGMT decreased by 3.9 and 40.8%, respectively, while H3K36me3 level was 1.7 times higher in PBLCs of PAH-exposed group compared to control group (all P < 0.001). These three epigenetic marks were significantly associated with DNA damage degree (all P < 0.001) and PAH exposure level in a dose–response manner (all P < 0.001). LINE-1 hypomethylation is correlated with enhanced H3K36me3 modification (β = −0.198, P = 0.002), indicating a synergistic effect between histone modification and DNA methylation at the whole genome level. In addition, MGMT expression was positively correlated with H3K36me3 modification (r = 0.253, P < 0.001), but not negatively correlated with MGMT methylation (r = 0.202, P < 0.05). The in vitro study using human bronchial epithelial cells treated with the organic extract of coke oven emissions confirmed that H3K36me3 is important for MGMT expression following PAH exposure. In summary, our study indicates that histone modification and DNA methylation might have synergistic effects on DNA damage induced by PAH exposure at the whole genome level and H3K36me3 is more essential for MGMT expression during the course.

中文翻译：

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PAH暴露工人外周血淋巴细胞中H3K36me3修饰与LINE-1和MGMT甲基化的关系

摘要

为了探索多环芳烃 (PAH) 暴露后 DNA 损伤引起的表观遗传改变以及不同表观遗传规则之间的串扰，我们检测了组蛋白 H3 (H3K36me3) 的三甲基化 Lys 36 和“长散在元素-1”(LINE-1) 的甲基化）'和'O ^{6 -}甲基鸟嘌呤-DNA甲基转移酶（MGMT）'在173名焦炉工人（PAH暴露组）和94名未暴露工人（对照组）的外周血淋巴细胞（PBLC）中。PAH 暴露组表现出更高的内部 PAH 暴露水平，增强的 DNA 损伤和增加的 MGMT 表达（所有P  < 0.001）。值得注意的是，LINE-1和MGMT的甲基化分别降低了 3.9% 和 40.8%，而与对照组相比，PAH 暴露组 PBLC 中的 H3K36me3 水平高 1.7 倍（均P  < 0.001）。这三个表观遗传标记与 DNA 损伤程度（均P  < 0.001）和 PAH 暴露水平呈剂量反应关系（均P  < 0.001）。LINE-1低甲基化与增强的 H3K36me3修饰相关（β = -0.198，P  = 0.002），表明在全基因组水平上组蛋白修饰和 DNA 甲基化之间存在协同效应。此外，MGMT 表达与 H3K36me3 修饰呈正相关（r  = 0.253，P < 0.001)，但与MGMT甲基化无负相关( r  = 0.202, P  < 0.05)。在体外使用与焦炉排放的有机提取物处理的人支气管上皮细胞研究证实，H3K36me3为以下PAH曝光MGMT表达重要。总之，我们的研究表明，组蛋白修饰和 DNA 甲基化可能在全基因组水平对 PAH 暴露诱导的 DNA 损伤具有协同作用，并且 H3K36me3 在此过程中对 MGMT 表达更为重要。