Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr 14.
Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals.
胞嘧啶甲基化是哺乳动物基因组 DNA 的主要共价修饰，在转录调控中发挥重要作用。然而，这种表观遗传标记酶促去除的分子机制仍难以捉摸。在这里，我们表明 5-甲基胞嘧啶 (5mC) 羟化酶 TET1 通过将 5mC 转化为 5-羟甲基胞嘧啶 (5hmC)，促进哺乳动物细胞中的 DNA 去甲基化，这一过程需要碱基切除修复途径。尽管单独表达 12 种已知的人类 DNA 糖苷酶不会增强哺乳动物细胞中 5hmC 的去除，但 AID（激活诱导的脱氨酶）/APOBEC（载脂蛋白 B mRNA 编辑酶复合物）家族的胞嘧啶脱氨酶可促进外源性和内源性 5hmC 的去甲基化。此外，Tet1 和 Apobec1 参与了成年小鼠大脑齿状回中神经元活性诱导的、区域特异性的、活性 DNA 去甲基化和随后的基因表达。我们的研究表明，在哺乳动物中，TET1 诱导的氧化脱氨机制可实现活性 DNA 去甲基化。
