Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism.
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.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China, Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China, The Novo Nordisk Foundation Center for Protein Research, Ubiquitin Signalling Group, Faculty of Health Sciences, Blegdamsvej 3b, 2200, Copenhagen, Denmark and Group of DNA Metabolism, The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Bailin
B
Zhao
Ying
Y
Yang
Xiaoli
X
Wang
Zechen
Z
Chong
Ruichuan
R
Yin
Shu-Hui
SH
Song
Chao
C
Zhao
Cuiping
C
Li
Hua
H
Huang
Bao-Fa
BF
Sun
Danni
D
Wu
Kang-Xuan
KX
Jin
Maoyong
M
Song
Ben-Zhan
BZ
Zhu
Guibin
G
Jiang
Jannie M
JM
Rendtlew Danielsen
Guo-Liang
GL
Xu
Yun-Gui
YG
Yang
Hailin
H
Wang
D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D001052:Apoferritins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002703:Chloranil / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D011809:Quinones; C540839:TET1 protein, mouse; D002703:Chloranil; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D001052:Apoferritins; D007501:Iron; D049308:Dioxygenases; C551914:Tet2 protein, mouse