Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells.
Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells.
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DOI：
10.1186/s13059-015-0685-2
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发表时间：
2015-06-02
期刊：
影响因子：
12.3
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Li Z;Dai H;Martos SN;Xu B;Gao Y;Li T;Zhu G;Schones DE;Wang Z
DNA甲基化模式是由从头DNA甲基转移酶DNMT3a/3b在早期胚胎低甲基化基因组中的CG二核苷酸中添加甲基来启动的。这些模式在DNA复制期间由DNMT1忠实地保持，以确保表观遗传在世代之间遗传。然而，这种两步走的模型基于有限的数据。我们为一系列DNMT基因敲除的胚胎干细胞生成了碱基分辨率的DNA甲基组，并在高度重复的元件上进行了深度覆盖。我们发现DNMT1和DNMT3a/3b的活性在建立对称的CG甲基化和CHH(H=A、T或C)甲基化方面是互补且同时起作用的。DNMT3a/3b可以在DNA复制的每个周期后在子链上添加甲基。我们还观察到DNMT1和DNMT3a/3b在分别抑制反转录转座子长末端重复和长散布元件方面意外地分工。我们的数据表明，哺乳动物细胞使用特定的CG密度阈值来预先确定野生型细胞中的甲基化水平和DNMT基因敲除细胞中甲基化减少的幅度。在低甲基化的基因组中，只有低CG密度的基因才能被诱导，或者令人惊讶地被抑制。最后，我们没有发现基因体甲基化和转录活性之间的任何联系。我们展示了DNMT酶在甲基化模式的建立和维持中的协同作用。DNMT1依赖和独立甲基化模式在基因组稳定性和转录调控中的不同作用的发现为理解生殖细胞发育、神经元多样性和跨代表观遗传提供了新的见解，并将有助于开发下一代DNMT抑制剂。本文的在线版本(doi：10.1186/s13059-0150685-2)包含补充材料，授权用户可以使用。
DNA methylation patterns are initiated by de novo DNA methyltransferases DNMT3a/3b adding methyl groups to CG dinucleotides in the hypomethylated genome of early embryos. These patterns are faithfully maintained by DNMT1 during DNA replication to ensure epigenetic inheritance across generations. However, this two-step model is based on limited data. We generated base-resolution DNA methylomes for a series of DNMT knockout embryonic stem cells, with deep coverage at highly repetitive elements. We show that DNMT1 and DNMT3a/3b activities work complementarily and simultaneously to establish symmetric CG methylation and CHH (H = A, T or C) methylation. DNMT3a/3b can add methyl groups to daughter strands after each cycle of DNA replication. We also observe an unexpected division of labor between DNMT1 and DNMT3a/3b in suppressing retrotransposon long terminal repeats and long interspersed elements, respectively. Our data suggest that mammalian cells use a specific CG density threshold to predetermine methylation levels in wild-type cells and the magnitude of methylation reduction in DNMT knockout cells. Only genes with low CG density can be induced or, surprisingly, suppressed in the hypomethylated genome. Lastly, we do not find any association between gene body methylation and transcriptional activity. We show the concerted actions of DNMT enzymes in the establishment and maintenance of methylation patterns. The finding of distinct roles of DNMT1-dependent and -independent methylation patterns in genome stability and regulation of transcription provides new insights for understanding germ cell development, neuronal diversity, and transgenerational epigenetic inheritance and will help to develop next-generation DNMT inhibitors. The online version of this article (doi:10.1186/s13059-015-0685-2) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
Huff JT;Zilberman D
通讯作者：
Zilberman D
影响因子：
5.3
作者：
Liang, GG;Chan, MF;Jones, PA
通讯作者：
Jones, PA
DOI：
10.1126/science.1190614
发表时间：
2010-10-29
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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通讯作者：
Reik W
影响因子：
64.8
作者：
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影响因子：
4.7
作者：
Chik, Flora;Szyf, Moshe
通讯作者：
Szyf, Moshe