Ascorbate Induces Ten-Eleven Translocation (Tet) Methylcytosine Dioxygenase-mediated Generation of 5-Hydroxymethylcytosine

作者：Minor, Emily A.; Court, Brenda L.; Young, Juan I.; Wang, Gaofeng^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(19): 13669-13674.

DOI：10.1074/jbc.C113.464800

• EMBRYONIC STEM-CELLS
• VITAMIN-C
• DNA DEMETHYLATION
• 5-METHYLCYTOSINE
• BRAIN
• SPECIFICATION
• HYDROXYLATION
• CONVERSION
• TRANSPORT
• PROTEINS

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.

• 出版日期2013-5-10