Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism

• Published in: Nucleic acids research Vol. 42; no. 3; pp. 1593 - 1605
• Main Authors: Zhao, Bailin, Yang, Ying, Wang, Xiaoli, Chong, Zechen, Yin, Ruichuan, Song, Shu-Hui, Zhao, Chao, Li, Cuiping, Huang, Hua, Sun, Bao-Fa, Wu, Danni, Jin, Kang-Xuan, Song, Maoyong, Zhu, Ben-Zhan, Jiang, Guibin, Rendtlew Danielsen, Jannie M, Xu, Guo-Liang, Yang, Yun-Gui, Wang, Hailin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.02.2014
• Subjects: 5-Methylcytosine - metabolism; Animals; Apoferritins - biosynthesis; Apoferritins - genetics; Cell Line; Cell Line, Tumor; Chloranil - pharmacology; Cytosine - analogs & derivatives; Cytosine - metabolism; Dioxygenases - metabolism; DNA Methylation - drug effects; DNA-Binding Proteins - genetics; Gene Expression Regulation; Gene Regulation, Chromatin and Epigenetics; Genome; Humans; Iron - metabolism; Mice; Oxidation-Reduction; Proto-Oncogene Proteins - genetics; Quinones - chemistry; Quinones - pharmacology
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkt1090

DNA methylation has been proven to be a critical epigenetic mark important for various cellular processes. Here, we report that redox-active quinones, a ubiquitous class of chemicals found in natural products, cancer therapeutics and environment, stimulate the conversion of 5 mC to 5 hmC in vivo, and increase 5 hmC in 5751 genes in cells. 5 hmC increase is associated with significantly altered gene expression of 3414 genes. Interestingly, in quinone-treated cells, labile iron-sensitive protein ferritin light chain showed a significant increase at both mRNA and protein levels indicating a role of iron regulation in stimulating Tet-mediated 5 mC oxidation. Consistently, the deprivation of cellular labile iron using specific chelator blocked the 5 hmC increase, and a delivery of labile iron increased the 5 hmC level. Moreover, both Tet1/Tet2 knockout and dimethyloxalylglycine-induced Tet inhibition diminished the 5 hmC increase. These results suggest an iron-regulated Tet-dependent DNA demethylation mechanism mediated by redox-active biomolecules.