Global H3K79 di-methylation mediates DNA damage response to PAH exposure in Chinese coke oven workers.
Global H3K79 di-methylation mediates DNA damage response to PAH exposure in Chinese coke oven workers.
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DOI：
10.1016/j.envpol.2020.115956
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发表时间：
2020-10
影响因子：
8.9
通讯作者：
Zhengbao Zhang;X. Xing;Shuyun Jiang;C. Qiu;Ziying Mo;Shen Chen;Li-ping Chen;Qing Wang;Yong-mei Xiao;Guanghui Dong;Yu-xin Zheng;Wen Chen;Daochuan Li
中科院分区：
文献类型：
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作者：
Zhengbao Zhang;X. Xing;Shuyun Jiang;C. Qiu;Ziying Mo;Shen Chen;Li-ping Chen;Qing Wang;Yong-mei Xiao;Guanghui Dong;Yu-xin Zheng;Wen Chen;Daochuan Li
多环芳烃（PAHs）是焦炉煤气中的主要污染物，可引起焦炉工人严重的遗传损伤。表观遗传变异在多环芳烃DNA损伤效应的调控中起着重要作用。先前的研究表明，H3 K79二甲基化（H3 K79 me 2）在DNA损伤修复中是不可或缺的。然而，H3 K79 me 2在多环芳烃暴露后的DNA损伤反应（DDR）中的潜在作用尚不清楚。本研究对256名焦炉工和对照组进行了外周血淋巴细胞H3 K79 me 2和DNA损伤的检测。结果表明，焦炉工人H3 K79 me 2总体水平比对照组低29.3%（P< 0.001）。H3 K79 me 2与尿1-羟基芘（1-OHP）浓度呈负相关（β=-0.235，P < 0.001），与彗星试验检测的遗传损伤程度呈负相关（β TailDNA %=-0.313，P < 0.001;βOTM=-0.251，P = 0.008）。因此，我们发现苯并（a）芘（BaP）抑制H3 K79 me 2在永生化的人支气管上皮细胞（HBE）以时间依赖的方式。为了探讨H3 K79 me 2在多环芳烃DDR中的作用，我们建立了组蛋白3.1/3.3K79A突变体细胞（H3 K79 A）来抑制H3 K79 me 2。BaP处理后H3 K79 A细胞DNA损伤较对照组严重，细胞活力下降。此外，我们还发现，DOT 1 L的表达，在H3 K79中唯一的甲基转移酶，抑制BaP剂量依赖性。DOT 1 L基因敲低导致BaP暴露后H3 K79 me 2水平降低，DNA损伤加重。这表明BaP通过抑制DOT 1 L表达诱导H3 K79 me 2阻遏。总之，这些研究结果表明，多环芳烃暴露降低了全球H3 K79 me 2的水平，这是不可或缺的DNA损伤反应调节的多环芳烃。
Polycyclic aromatic hydrocarbons (PAHs) are the main contaminants of coke oven emissions which can induce serious genetic damage in coke oven workers. Epigenetic alternations play essential roles in the regulation of DNA damage effect of PAHs. Previous studies indicate that H3K79 di-methylation (H3K79me2) is integral in DNA damage repair. However, the potential role of H3K79me2 in DNA damage response (DDR) following PAHs exposure is still unclear. In this study, we recruited 256 male coke oven workers and control workers, and examined H3K79me2 and DNA damage in their peripheral blood lymphocytes (PBLCs). The results showed that global H3K79me2 of coke oven workers was 29.3% less than that of the controls (P< 0.001). The H3K79me2 was negatively correlated with the concentration of urinary 1-hydroxypyrene (1-OHP) (β= -0.235,P< 0.001) and level of genetic damage evaluated by comet assay (βTail DNA %= -0.313,P< 0.001;βOTM= -0.251,P= 0.008). Consistently, we found that benzo(a)pyrene (BaP) inhibited H3K79me2 in immortalized human bronchial epithelial (HBE) cells in a time-dependent manner. In order to explore the function of H3K79me2 in PAHs DDR, we established histone 3.1/3.3 K79A mutant cells (H3K79 A) to suppress H3K79me2. H3K79 A cells showed more serious DNA damage and decreased cell viability than control cells after BaP treatment. In addition, we also found that the expression of DOT1L, the only methyltransferase in H3K79, was repressed by BaP dose-dependently. DOT1L knockdown resulted in decreased H3K79me2 level and aggravated DNA damage after BaP exposure. This suggests that BaP induces H3K79me2 repression via inhibiting DOT1L expression. In conclusion, these findings indicate that PAH exposure decreases the level of global H3K79me2, which is integral for DNA damage response regulation of PAHs.