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Chem Res Toxicol. 2016 Sep 19;29(9):1428-38. doi: 10.1021/acs.chemrestox.6b00090. Epub 2016 Aug 24.

Dynamic Interplay between the Transcriptome and Methylome in Response to Oxidative and Alkylating Stress.

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Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
ExxonMobil Petroleum and Chemicals , Hermeslaan 2, 1831 Machelen, Belgium.
Département de médecine nucléaire et radiobiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke , Sherbrooke, Québec, Canada J1H 5N4.


In recent years, it has been shown that free radicals not only react directly with DNA but also regulate epigenetic processes such as DNA methylation, which may be relevant within the context of, for example, tumorigenesis. However, how these free radicals impact the epigenome remains unclear. We therefore investigated whether methyl and hydroxyl radicals, formed by tert-butyl hydroperoxide (TBH), change temporal DNA methylation patterns and how this interferes with genome-wide gene expression. At three time points, TBH-induced radicals in HepG2 cells were identified by electron spin resonance spectroscopy. Total 5-methylcytosine (5mC) levels were determined by liquid chromatography and tandem mass spectrometry and genome-wide changes in 5mC and gene expression by microarrays. Induced methylome changes rather represent an adaptive response to the oxidative stress-related reactions observed in the transcriptome. More specifically, we found that methyl radicals did not induce DNA methylation directly. An initial oxidative and alkylating stress-related response of the transcriptome during the early phase of TBH treatment was followed by an epigenetic response associated with cell survival signaling. Also, we identified genes of which the expression seems directly regulated by DNA methylation. This work suggests an important role of the methylome in counter-regulating primary oxidative and alkylating stress responses in the transcriptome to restore normal cell function. Altogether, the methylome may play an important role in counter-regulating primary oxidative and alkylating stress responses in the transcriptome presumably to restore normal cell function.

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