抗坏血酸诱导十号十一号转位（Tet）甲基胞嘧啶双加氧酶介导的 5-羟甲基胞嘧啶生成。
Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine.
机构信息
John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
出版信息
J Biol Chem. 2013 May 10;288(19):13669-74. doi: 10.1074/jbc.C113.464800. Epub 2013 Apr 2.
BACKGROUND
Tet methylcytosine dioxygenase converts 5-mC to 5-hmC in DNA.
RESULTS
Ascorbate significantly and specifically enhances Tet-mediated generation of 5-hmC.
CONCLUSION
Our findings suggest that ascorbate enhances 5-hmC generation, most likely by acting as a co-factor for Tet methylcytosine dioxygenase to generate 5-hmC.
SIGNIFICANCE
The availability of ascorbate could have significant consequences for health and diseases by modulating the epigenetic control of genome activity. Ascorbate (vitamin C) is best known for its role in scurvy, in which the hydroxylation of collagen catalyzed by dioxygenases is incomplete due to ascorbate deficiency. Here, we report a novel function of ascorbate in the hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA catalyzed by Tet (ten-eleven translocation) methylcytosine dioxygenase. The content of 5-hmC is extremely low in mouse embryonic fibroblasts cultured in ascorbate-free medium. Additions of ascorbate dose- and time-dependently enhance the generation of 5-hmC, without any effects on the expression of Tet genes. Treatment with another reducer glutathione (GSH) does not change the level of 5-hmC. Further, blocking ascorbate entry into cells by phloretin and knocking down Tet (Tet1, Tet2, and Tet3) expression by short interference RNAs (siRNA) significantly inhibit the effect of ascorbate on 5-hmC. These results suggest that ascorbate enhances 5-hmC generation, most likely by acting as a co-factor for Tet methylcytosine dioxygenase to hydroxylate 5-mC. Thus, we have uncovered a novel role for ascorbate in modulating the epigenetic control of genome activity.
背景
Tet 双加氧酶将 5-mC 转化为 DNA 中的 5-hmC。
结果
抗坏血酸显著且特异性地增强了 Tet 介导的 5-hmC 的生成。
结论
我们的发现表明，抗坏血酸通过作为 Tet 甲基胞嘧啶双加氧酶的辅助因子来生成 5-hmC，从而增强 5-hmC 的生成。
意义
抗坏血酸（维生素 C）的可用性可通过调节基因组活性的表观遗传控制，对健康和疾病产生重大影响。抗坏血酸因在坏血病中的作用而广为人知，在坏血病中，由于抗坏血酸缺乏，双加氧酶催化的胶原蛋白羟化作用不完全。在这里，我们报告了抗坏血酸在 Tet（十碳十一烯转移酶）甲基胞嘧啶双加氧酶催化的 DNA 中 5-甲基胞嘧啶（5-mC）向 5-羟甲基胞嘧啶（5-hmC）的羟化中的新功能。在不含抗坏血酸的培养基中培养的小鼠胚胎成纤维细胞中，5-hmC 的含量极低。抗坏血酸的添加剂量和时间依赖性地增强了 5-hmC 的生成，而对 Tet 基因的表达没有任何影响。用另一种还原剂谷胱甘肽（GSH）处理不会改变 5-hmC 的水平。此外，用 phloretin 阻断抗坏血酸进入细胞，并通过短干扰 RNA（siRNA）敲低 Tet（Tet1、Tet2 和 Tet3）表达，显著抑制了抗坏血酸对 5-hmC 的作用。这些结果表明，抗坏血酸通过作为 Tet 甲基胞嘧啶双加氧酶的辅助因子来增强 5-hmC 的生成，从而将 5-mC 羟化。因此，我们发现了抗坏血酸在调节基因组活性的表观遗传控制中的新作用。
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