Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain

被引：1055

作者：

Guo, Junjie U. ^{[1
,2
]}

Su, Yijing ^{[1
,3
]}

Zhong, Chun ^{[1
,3
]}

Ming, Guo-li ^{[1
,2
,3
]}

Song, Hongjun ^{[1
,2
,3
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

来源：

CELL | 2011年 / 145卷 / 03期

关键词：

SINGLE-STRANDED-DNA; METHYLATION; GLYCOSYLASE; GENOME; 5-HYDROXYMETHYLCYTOSINE; INHIBITOR; DEAMINASE; QUANTIFICATION; MECHANISMS; CONVERSION;

D O I：

10.1016/j.cell.2011.03.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：423 / 434

页数：12

共 55 条

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