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Benzene metabolite 1,2,4-benzenetriol changes DNA methylation and histone acetylation of erythroid-specific genes in K562 cells

Abstract

1,2,4-Benzenetriol (BT) is one of the phenolic metabolites of benzene, a general occupational hazard and ubiquitous environmental air pollutant with leukemogenic potential in humans. Previous studies have revealed that the benzene metabolites phenol and hydroquinone can inhibit hemin-induced erythroid differentiation in K562 cells. We investigated the roles of DNA methylation and histone acetylation in BT-inhibited erythroid differentiation in K562 cells. When K562 cells were treated with 0, 5, 10, 15 or 20 µM BT for 72 h, hemin-induced hemoglobin synthesis decreased in a concentration-dependent manner. Both 5-aza-2′-deoxycytidine (5-aza-CdR, DNA methyltransferase inhibitor) and trichostatin A (TSA, histone deacetylases inhibitor) could prevent 20 µM BT from inhibiting hemin-induced hemoglobin synthesis and the mRNA expression of erythroid genes. Exposure to BT changed DNA methylation levels at several CpG sites of erythroid-specific genes, as well as the acetylation of histone H3 and H4, chromatin occupancy of GATA-1 and recruitment of RNA polymerase II at α-globin and β-globin gene clusters after hemin induction. These results demonstrated that BT could inhibit hemin-induced erythroid differentiation, where DNA methylation and histone acetylation also played important roles by down-regulating erythroid-specific genes. This partly explained the mechanisms of benzene hematotoxicity.

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Acknowledgements

This work was supported by grants from Natural Science Foundation of China (Project nos. 81070091 and 81573192) and the Academic Excellence Foundation of BUAA for Ph.D. Students. We thank Miss Huimeng Wang for linguistic assistance during the preparation of this manuscript.

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Correspondence to Zong-Chun Yi.

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Yu, CH., Li, Y., Zhao, X. et al. Benzene metabolite 1,2,4-benzenetriol changes DNA methylation and histone acetylation of erythroid-specific genes in K562 cells. Arch Toxicol 93, 137–147 (2019). https://doi.org/10.1007/s00204-018-2333-6

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Keywords

  • 1,2,4-Benzenetriol
  • Erythroid differentiation
  • DNA methylation
  • Histone acetylation