The epigenetic role of vitamin C in health and disease

Abstract

Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.

Keywords: DNA methylation; Epigenetics; Histone methylation; JmjC domain-containing histone demethylases; Methylcytosine dioxygenase; Scurvy; Vitamin C.

Fig. 1

Ascorbate and DNA demethylation. The methylation of an unmodified 5C could be established by DNMT1. 5mC can also be passively diluted by the failed maintenance during DNA synthesis. Ascorbate promotes the TET catalyzed cascade oxidation of 5mC, to 5hmC, to 5fC and to 5caC. Unable to maintain 5hmC in the newly synthesized DNA leads to the passive dilution of 5hmC. Both 5fC and 5caC could be excised by the DNA repair enzyme thymine DNA glycosylase to produce an abasic position, which is eventually replaced by an unmodified C, thus completing the process of DNA active demethylation and a cycle of DNA methylation-demethylation

Fig. 2

The epigenetic role of vitamin C in health and disease. The bioavailability of ascorbate influences health and diseases by regulating the demethylation of DNA and histone, further the transcriptome