维生素C对干细胞功能的影响

关键词： 维生素C丨干细胞

Tet 酶通过将5-甲基胞嘧啶 （5mC） 转化成5-羟甲基胞嘧啶 （5hmC） 和其他氧化的变体来调控DNA甲基化。在这项研究中，维生素C（与Tets属于同一家族的酶的一个辅因子）被发现是小鼠胚胎干细胞（这些细胞一般是在没有维生素C的情况下培养的）中Tet活性的一个直接调控因子。将维生素C添加到培养介质中导致5hmC含量增加和无数基因启动子的去甲基化。重塑的DNA甲基化和基因表达模式与发生在早期胚胎内细胞团块中的DNA去甲基化相似。

推荐英文摘要：

Nature doi: 10.1038/nature12362

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

Kathryn Blaschke, Kevin T. Ebata, Mohammad M. Karimi, Jorge A. Zepeda-Martínez, Preeti Goyal, Sahasransu Mahapatra, Angela Tam, Diana J. Laird, Martin Hirst, Anjana Rao, Matthew C. Lorincz & Miguel Ramalho-Santos

DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, ａnd the suppression of retrotransposons. Global DNA demethylation occurs in the early embryo ａnd the germ line, ａnd may be mediated by Tet （tenneleventranslocation） enzymes, which convert 5-methylcytosine （5mC） to 5-hydroxymethylcytosine （5hmC）7. Tet enzymes have been studied extensively in mouse embryonic stem （ES） cells, 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. Tet1 binding is enriched near the transcription start site of genes affected by vitamin C treatment. Importantly, vitamin C, but not other antioxidants, enhances the activity of recombinant Tet1 in a biochemical assay, ａnd the vitamin-C-induced changes in 5hmC ａnd 5mC are entirely suppressed in Tet1 ａnd Tet2 double knockout ES cells. Vitamin C has a stronger effect on regions that gain methylation in cultured ES cells compared to blastocysts, ａnd in vivo are methylated only after implantation. In contrast, imprinted regions ａnd intracisternal A particle retroelements, which are resistant to demethylation in the early embryo, are resistant to vitamin-C-induced DNA demethylation. Collectively, the results of this study establish vitamin?C as a direct regulator of Tet activity ａnd DNA methylation fidelity in ES cells.

原创作者：上海信裕生物科技有限公司