Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells

摘要

DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, and the suppression of retrotransposons~1 Global DNA demethylation occurs in the early embryo and the germ line~(2,3), and may be mediated by Tet (ten eleven translocation) enzymes~(4-6), which convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC)~7. Tet enzymes have been studied extensively in mouse embryonic stem (ES) cells~(8-12), which are generally cultured in the absence of vitamin C, a potential cofactor for Fe(Ⅱ) 2-oxoglutarate dioxygenase enzymes such as Tet enzymes. Here we report that addition of vitamin C to mouse ES cells promotes Tet activity, leading to a rapid and global increase in 5hmC. This is followed by DNA demethylation of many gene promoters and upregulation of demethylated germline genes.