Regulation of the Epigenome by Vitamin C

Abstract

Emerging evidence suggests that ascorbate, the dominant form of vitamin C under physiological pH conditions, influences activity of the genome via regulating epigenomic processes. Ascorbate serves as a cofactor for Ten-eleven translocation (TET) dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and further to 5-formylcytosine (5fC) and to 5-carboxylcytosine (5caC), which are ultimately replaced by unmodified cytosine. The Jumonji C (JmjC)-domain-containing histone demethylases also require ascorbate as a cofactor for histone demethylation. Thus, by primarily participating in the demethylation of both DNA and histones, ascorbate appears to be a mediator of the interface between the genome and environment. Furthermore, redox status has a profound impact on the bioavailability of ascorbate in the nucleus. In order to bridge the gap between redox biology and genomics, we suggest an interdisciplinary research field that can be termed redox genomics to study dynamic redox processes in health and diseases. This review examines the evidence and potential molecular mechanism of ascorbate in the demethylation of the genome, and it highlights potential epigenetic roles of ascorbate in various diseases.

Keywords: DNA demethylation; JmjC-domain-containing histone demethylase; Ten-eleven translocation dioxygenase; histone demethylation; iron- and 2-oxoglutarate-dependent dioxygenase; vitamin C.

Figure 1. The role of ascorbate in DNA demethylation

As a cofactor, ascorbate participates in the cascade oxidation of 5mC, to 5hmC, to 5fC and to 5caC catalyzed by TET dioxygenases. 5fC and 5caC are then replaced by unmodified 5C by BER machinery. Additionally, unable to maintain 5hmC in the newly synthesized DNA also leads to passive demethylation. The methylation of an unmodified 5C could be reestablished by DNMT1, thus complete a cycle of DNA methylation–demethylation.

Figure 2. The role of ascorbate in histone demethylation

As a cofactor for Jmjc domain-containing histone demethylases (JmjC), ascorbate participates in the oxidation of tri-methylated, di-methylated and mono-methylated lysine in histones, which is followed by a spontaneous removal of the hydroxymethyl group. The methylation of an unmodified lysine in histones could be reestablished by HMT, thus complete a cycle of histone methylation–demethylation.