Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals
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- 作者：Ruichuan Yin ; Shi-Qing Mao ; Bailin Zhao ; Zechen Chong ; Ying Yang ; Chao Zhao ; Dapeng Zhang ; Hua Huang ; Juan Gao ; Zheng Li ; Yan Jiao ; Cuiping Li ; Shengquan Liu ; Danni Wu ; Weikuan Gu ; Yun-Gui Yang ; Guo-Liang Xu ; Hailin Wang
- 刊名：The Journal of the American Chemical Society
- 出版年：2013
- 出版时间：July 17, 2013
- 年：2013
- 卷：135
- 期：28
- 页码：10396-10403
- 全文大小：459K
- 年卷期：v.135,no.28(July 17, 2013)
- ISSN：1520-5126
文摘
DNA hydroxymethylation and its mediated DNA demethylation are critical for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidation of 5-methylcytosine (5mC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidation-resistant derivatives, we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe2+. Other strong reducing chemicals do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5mC oxidation products, particularly 5-formylcytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5mC (40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5mC oxidation nor the overall level of 5mC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5mC oxidation and DNA demethylation are also observed in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications.