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Background and Aims: Multiple regulatory mechanisms play an important role in arsenic-induced liver injury. To in-vestigate whether histone H3 lysine 4 (H3K4) methyltrans-ferase (SET7/9) and histone H3K4 demethyltransferase (LSD1/KDM1A) can regulate endoplasmic reticulum stress (ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic. Methods: Apoptosis, proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer. The expres-sion of ERS- and epigenetic-related proteins was detected by Western blot analysis. The antisense SET7/9 expres-sion vector and the overexpressed LSD1 plasmid were used for transient transfection of LO2 cells. The effects of NaAsO2 on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein, activating transcrip-tion factor 4 and C/EBP-homologous protein were evalu-ated by chromatin immunoprecipitation assay. Results: The protein expression of LSD1 (1.25±0.08 vs. 1.77±0.08, p=0.02) was markedly decreased by treatment with 100 μM NaAsO2, whereas the SET7/9 (0.68±0.05 vs. 1.10±0.13, p=0.002) expression level was notably increased, which resulted in increased H3K4me1/2 (0.93±0.64, 1.19±0.22 vs. 0.71±0.13, 0.84±0.13, p=0.03 and p=0.003). After silencing SET7/9 and overexpressing LSD1 by transfec-tion, apoptosis rate (in percentage: 3.26±0.34 vs. 7.04± 0.42, 4.80±0.32 vs. 7.52±0.38, p=0.004 and p=0.02) was significantly decreased and proliferation rate was no-tably increased, which is reversed after inhibiting LSD1 (in percentage: 9.31±0.40 vs. 7.52±0.38, p=0.03). Further-more, the methylation levels of H3 in the promoter regions of GRP78 (20.80±2.40 vs. 11.75±2.47, 20.46±2.23 vs. 14.37±0.91, p=0.03 and p=0.01) and CHOP (48.67±4.04 vs. 16.67±7.02, 59.33±4.51 vs. 20.67±3.06, p=0.004 and p=0.001) were significantly increased in LO2 cells ex-posed to 100 μM NaAsO2 for 24 h. Conclusions: Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis. NaAsO2 induces apoptosis in LO2 cells by activating the ERS-mediated apoptotic signal-ing pathway, at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes, including GRP78 and CHOP.