title: Dynamic Interplay between the Transcriptome and Methylome in Response to Oxidative and Alkylating Stress.
abstract: 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.
authors: 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.
authors: Lize
authors: L
authors: Deferme
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Jarno E J
authors: JE
authors: Wolters
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Sandra M H
authors: SM
authors: Claessen
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Daniel H J
authors: DH
authors: Theunissen
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Twan
authors: T
authors: van den Beucken
authors: Département de médecine nucléaire et radiobiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke , Sherbrooke, Québec, Canada J1H 5N4.
authors: J Richard
authors: JR
authors: Wagner
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Simone G
authors: SG
authors: van Breda
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Jos C S
authors: JC
authors: Kleinjans
authors: Department of Toxicogenomics, School of Oncology and Developmental Biology (GROW), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors: Jacco J
authors: JJ
authors: Briedé
mesh_terms: D000478:Alkylation; D002853:Chromatography, Liquid; D019175:DNA Methylation; D005609:Free Radicals / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics*; D021241:Spectrometry, Mass, Electrospray Ionization; D013312:Stress, Physiological / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D005609:Free Radicals