title: Oxidative stress alters global histone modification and DNA methylation.
abstract: The JmjC domain-containing histone demethylases can remove histone lysine methylation and thereby regulate gene expression. The JmjC domain uses iron Fe(II) and α-ketoglutarate (αKG) as cofactors in an oxidative demethylation reaction via hydroxymethyl lysine. We hypothesize that reactive oxygen species will oxidize Fe(II) to Fe(III), thereby attenuating the activity of JmjC domain-containing histone demethylases. To minimize secondary responses from cells, extremely short periods of oxidative stress (3h) were used to investigate this question. Cells that were exposed to hydrogen peroxide (H2O2) for 3h exhibited increases in several histone methylation marks including H3K4me3 and decreases of histone acetylation marks including H3K9ac and H4K8ac; preincubation with ascorbate attenuated these changes. The oxidative stress level was measured by generation of 2',7'-dichlorofluorescein, GSH/GSSG ratio, and protein carbonyl content. A cell-free system indicated that H2O2 inhibited histone demethylase activity where increased Fe(II) rescued this inhibition. TET protein showed a decreased activity under oxidative stress. Cells exposed to a low-dose and long-term (3 weeks) oxidative stress also showed increased global levels of H3K4me3 and H3K27me3. However, these global methylation changes did not persist after washout. The cells exposed to short-term oxidative stress also appeared to have higher activity of class I/II histone deacetylase (HDAC) but not class III HDAC. In conclusion, we have found that oxidative stress transiently alters the epigenetic program process through modulating the activity of enzymes responsible for demethylation and deacetylation of histones.
authors: Occupational Disease and Toxicology Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China 100020.
authors: Yingmei
authors: Y
authors: Niu
authors: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors: Thomas L
authors: TL
authors: DesMarais
authors: Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China 100020. Electronic address: tongzhh@hotmail.com.
authors: Zhaohui
authors: Z
authors: Tong
authors: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA; Shanghai Jiao-Tong University School of Public Health, Shanghai, China 200025. Electronic address: yixin.yao@nyumc.org.
authors: Yixin
authors: Y
authors: Yao
authors: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 100016, USA. Electronic address: max.costa@nyumc.org.
authors: Max
authors: M
authors: Costa
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D019175:DNA Methylation / Q000502:physiology*; D049308:Dioxygenases / Q000378:metabolism; D005290:Ferric Compounds / Q000378:metabolism; D005296:Ferrous Compounds / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds; D006657:Histones; D006861:Hydrogen Peroxide; D007501:Iron; D049308:Dioxygenases; D056484:Jumonji Domain-Containing Histone Demethylases; D006655:Histone Deacetylases; D001205:Ascorbic Acid; D010100:Oxygen
keywords: Histone demethylase; Hydrogen peroxide; Oxidative stress
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