Identification of genetic elements that autonomously determine DNA methylation states

被引：286

作者：

Lienert, Florian ^{[1
,2
]}

Wirbelauer, Christiane ^{[1
]}

Som, Indrani ^{[3
]}

Dean, Ann ^{[3
]}

Mohn, Fabio ^{[1
]}

Schuebeler, Dirk ^{[1
,2
]}

机构：

[1] Friedrich Miescher Inst Biomed Res, Basel, Switzerland

[2] Univ Basel, Fac Sci, Basel, Switzerland

[3] NIDDKD, Cellular & Dev Biol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 11期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

EMBRYONIC STEM-CELLS; CPG ISLANDS; CHROMATIN-STRUCTURE; HISTONE; METHYLTRANSFERASE; NANOG; TRANSCRIPTION; PLURIPOTENT; METHYLOME; PROMOTER;

D O I：

10.1038/ng.946

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Cytosine methylation is a repressive, epigenetically propagated DNA modification. Although patterns of DNA methylation seem tightly regulated in mammals, it is unclear how these are specified and to what extent this process entails genetic or epigenetic regulation. To dissect the role of the underlying DNA sequence, we sequentially inserted over 50 different DNA elements into the same genomic locus in mouse stem cells. Promoter sequences of approximately 1,000 bp autonomously recapitulated correct DNA methylation in pluripotent cells. Moreover, they supported proper de novo methylation during differentiation. Truncation analysis revealed that this regulatory potential is contained within small methylation-determining regions (MDRs). MDRs can mediate both hypomethylation and de novo methylation in cis, and their activity depends on developmental state, motifs for DNA-binding factors and a critical CpG density. These results demonstrate that proximal sequence elements are both necessary and sufficient for regulating DNA methylation and reveal basic constraints of this regulation.

引用

页码：1091 / U78

页数：8

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