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

Bailin Zhao; Ying Yang; Xiaoli Wang; Zechen Chong; Ruichuan Yin; Shu-Hui Song; Chao Zhao; Cuiping Li; Hua Huang; Bao-Fa Sun; Danni Wu; Kang-Xuan Jin; Maoyong Song; Ben-Zhan Zhu; Guibin Jiang; Jannie Michaela Rendtlew Danielsen; Guo-Liang Xu; Yun-Gui Yang; Hailin Wang

doi:10.1093/nar/gkt1090

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

Bailin Zhao, Ying Yang, Xiaoli Wang, Zechen Chong, Ruichuan Yin, Shu-Hui Song, Chao Zhao, Cuiping Li, Hua Huang, Bao-Fa Sun, Danni Wu, Kang-Xuan Jin, Maoyong Song, Ben-Zhan Zhu, Guibin Jiang, Jannie Michaela Rendtlew Danielsen, Guo-Liang Xu, Yun-Gui Yang, Hailin Wang

Novo Nordisk Foundation Center for Protein Research

76 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nucleic Acids Research
Volume	42
Issue number	3
Pages (from-to)	1593-1605
Number of pages	13
ISSN	0305-1048
DOIs	https://doi.org/10.1093/nar/gkt1090
Publication status	Published - Feb 2014

Keywords

5-Methylcytosine
Animals
Apoferritins
Cell Line
Cell Line, Tumor
Chloranil
Cytosine
DNA Methylation
DNA-Binding Proteins
Dioxygenases
Gene Expression Regulation
Genome
Humans
Iron
Mice
Oxidation-Reduction
Proto-Oncogene Proteins
Quinones

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zhao, B., Yang, Y., Wang, X., Chong, Z., Yin, R., Song, S-H., Zhao, C., Li, C., Huang, H., Sun, B-F., Wu, D., Jin, K-X., Song, M., Zhu, B-Z., Jiang, G., Danielsen, J. M. R., Xu, G-L., Yang, Y-G., & Wang, H. (2014). Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism. Nucleic Acids Research, 42(3), 1593-1605. https://doi.org/10.1093/nar/gkt1090

Zhao, B, Yang, Y, Wang, X, Chong, Z, Yin, R, Song, S-H, Zhao, C, Li, C, Huang, H, Sun, B-F, Wu, D, Jin, K-X, Song, M, Zhu, B-Z, Jiang, G, Danielsen, JMR, Xu, G-L, Yang, Y-G & Wang, H 2014, 'Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism', Nucleic Acids Research, vol. 42, no. 3, pp. 1593-1605. https://doi.org/10.1093/nar/gkt1090

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

abstract = "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.",

keywords = "5-Methylcytosine, Animals, Apoferritins, Cell Line, Cell Line, Tumor, Chloranil, Cytosine, DNA Methylation, DNA-Binding Proteins, Dioxygenases, Gene Expression Regulation, Genome, Humans, Iron, Mice, Oxidation-Reduction, Proto-Oncogene Proteins, Quinones",

author = "Bailin Zhao and Ying Yang and Xiaoli Wang and Zechen Chong and Ruichuan Yin and Shu-Hui Song and Chao Zhao and Cuiping Li and Hua Huang and Bao-Fa Sun and Danni Wu and Kang-Xuan Jin and Maoyong Song and Ben-Zhan Zhu and Guibin Jiang and Danielsen, {Jannie Michaela Rendtlew} and Guo-Liang Xu and Yun-Gui Yang and Hailin Wang",

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T1 - Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism

AU - Zhao, Bailin

AU - Yang, Ying

AU - Wang, Xiaoli

AU - Chong, Zechen

AU - Yin, Ruichuan

AU - Song, Shu-Hui

AU - Zhao, Chao

AU - Li, Cuiping

AU - Huang, Hua

AU - Sun, Bao-Fa

AU - Wu, Danni

AU - Jin, Kang-Xuan

AU - Song, Maoyong

AU - Zhu, Ben-Zhan

AU - Jiang, Guibin

AU - Danielsen, Jannie Michaela Rendtlew

AU - Xu, Guo-Liang

AU - Yang, Yun-Gui

AU - Wang, Hailin

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

KW - 5-Methylcytosine

KW - Animals

KW - Apoferritins

KW - Cell Line

KW - Cell Line, Tumor

KW - Chloranil

KW - Cytosine

KW - DNA Methylation

KW - DNA-Binding Proteins

KW - Dioxygenases

KW - Gene Expression Regulation

KW - Genome

KW - Humans

KW - Iron

KW - Mice

KW - Oxidation-Reduction

KW - Proto-Oncogene Proteins

KW - Quinones

U2 - 10.1093/nar/gkt1090

DO - 10.1093/nar/gkt1090

M3 - Journal article

C2 - 24214992

SN - 0305-1048

VL - 42

SP - 1593

EP - 1605

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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