Association between H3K36me3 modification and methylation of LINE-1 and MGMT in peripheral blood lymphocytes of PAH-exposed workers

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.

Keywords: DNA damage; H3K36me3; LINE-1 methylation; MGMT methylation; occupational PAH exposure.