Hydroquinone Increases 5-Hydroxymethylcytosine Formation through Ten Eleven Translocation 1 (TET1) 5-Methylcytosine Dioxygenase
Hydroquinone Increases 5-Hydroxymethylcytosine Formation through Ten Eleven Translocation 1 (TET1) 5-Methylcytosine Dioxygenase
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DOI：
10.1074/jbc.m113.491365
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发表时间：
2013-10-04
影响因子：
4.8
通讯作者：
Bressler, Joseph P.
中科院分区：
文献类型：
--
作者：
Coulter, Jonathan B.;O'Driscoll, Cliona M.;Bressler, Joseph P.
DNA 甲基化在整个发育过程以及癌症和神经系统疾病等多种病理学中调节基因表达。众所周知，控制甲基化动态水平和目标的途径会被化学物质破坏，因此在预防和临床方面都引起了极大的兴趣。苯及其代谢物氢醌已被证明会导致 DNA 甲基化水平降低，但其机制尚不清楚。本研究采用细胞培养模型来研究对苯二酚介导的 DNA 甲基化变化的机制。不影响 HEK293 细胞活力的暴露会导致基因组和甲基化报告 DNA 去甲基化。对苯二酚引起甲基化报告质粒的重新激活，而添加 N-乙酰半胱氨酸可防止这种情况发生。对苯二酚还导致 10-11 易位 1 活性和 5-羟甲基胞嘧啶整体水平增加。在 5-羟甲基胞嘧啶和 5-甲基胞嘧啶均减少之前，发现 5-羟甲基胞嘧啶在 LINE-1 处富集。 10-11易位-1敲除减少了对苯二酚暴露后5-羟甲基胞嘧啶的形成以及谷氨酸-半胱氨酸连接酶催化亚基和14-3-3西格玛的诱导。最后，111 易位 1 敲除降低了暴露于对苯二酚后积累在 G(2)+M 中的细胞百分比，表明它可能在响应毒物的细胞周期变化中发挥作用。这项工作表明，接触氢醌会导致 HEK293 细胞中活性且功能性的 DNA 去甲基化，其机制涉及活性氧和 10-11 易位 1 5-甲基胞嘧啶双加氧酶。
DNA methylation regulates gene expression throughout development and in a wide range of pathologies such as cancer and neurological disorders. Pathways controlling the dynamic levels and targets of methylation are known to be disrupted by chemicals and are therefore of great interest in both prevention and clinical contexts. Benzene and its metabolite hydroquinone have been shown to lead to decreased levels of DNA methylation, although the mechanism is not known. This study employs a cell culture model to investigate the mechanism of hydroquinone-mediated changes in DNA methylation. Exposures that do not affect HEK293 cell viability led to genomic and methylated reporter DNA demethylation. Hydroquinone caused reactivation of a methylated reporter plasmid that was prevented by the addition of N-acetylcysteine. Hydroquinone also caused an increase in Ten Eleven Translocation 1 activity and global levels of 5-hydroxymethylcytosine. 5-Hydroxymethylcytosine was found enriched at LINE-1 prior to a decrease in both 5-hydroxymethylcytosine and 5-methylcytosine. Ten Eleven Translocation-1 knockdown decreased 5-hydroxymethylcytosine formation following hydroquinone exposure as well as the induction of glutamate-cysteine ligase catalytic subunit and 14-3-3 sigma. Finally, Ten Eleven Translocation 1 knockdown decreased the percentage of cells accumulating in G(2)+M following hydroquinone exposure, indicating that it may have a role in cell cycle changes in response to toxicants. This work demonstrates that hydroquinone exposure leads to active and functional DNA demethylation in HEK293 cells in a mechanism involving reactive oxygen species and Ten Eleven Translocation 1 5-methylcytosine dioxygenase.