Epigenetic Regulation by Vitamin C

Sci. Signal.  21 May 2013:
Vol. 6, Issue 276, pp. ec113
DOI: 10.1126/scisignal.2004337

Vitamin C is an essential nutrient that functions as an enzymatic cofactor and as an antioxidant. The ten-eleven translocation (Tet) family of dioxygenases, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), are epigenetic regulators of gene expression that mediate DNA demethylation. Tet genes are highly expressed in embryonic tissues, and Tet dysfunction is associated with oncogenesis and metastasis. Minor et al. found that ascorbate (vitamin C) promoted the Tet-mediated generation of 5-hmC in mouse and human cells. The amount of 5-hmC in mouse embryonic fibroblasts (MEFs) and human cancer cell lines grown in medium lacking ascorbate was low, and the addition of ascorbate induced a rapid, sustained, and dose-dependent increase in the abundance of 5-hmC without affecting cell growth or the expression of Tet1, Tet2, or Tet3. Addition of glutathione (GSH), another antioxidant, did not affect 5-hmC abundance. Pretreatment with phloretin, a drug that inhibits the transporter-dependent uptake of ascorbate, prevented ascorbate-induced 5-hmC production but did not affect basal abundance. Knocking down Tet1, Tet2, and Tet3 reduced basal abundance of 5-hmC in MEFs and attenuated ascorbate-induced increase in 5-hmC generation. Thus, the findings suggest that vitamin C may contribute to epigenetic regulation of gene expression by functioning as a cofactor for Tet enzymes.

E. A. Minor, B. L. Court, J. I. Young, G. Wang, Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J. Biol. Chem. 288, 13669–13674 (2013). [Abstract] [Full Text]