非CPG甲基化在人体不同类型细胞基因组上的分布情况及其在样本间的变化

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发布日期：2012-09-19 09:51 文章来源：丁香园
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关键词： 甲基化 技术专题 欧易生物 丁香通 丁香园 　 点击次数：

众所周知，DNA甲基化在生物发育和染病中起到至关重要的作用。先前的研究主要集中于CpG的甲基化，如它在人和小鼠中占到总基因组甲基化的3/4，它的分布、功能和个体间的稳定性我们已经相当了解。但是，对于非CpG甲基化，即CpA、CpT和CpC二核苷酸甲基化知之甚少。本研究中，作者结合基因芯片、简化的表观亚硫酸氢盐测序技术（Reduced Representation Bisulfite Sequencing (RRBS) ）和基因敲除技术，并经定量PCR验证，得到大量实验数据，综合分析了人体76种不同细胞的基因组DNA甲基化图谱，他们包括具有分化潜能的干细胞和特化的体细胞等。结果发现，1、non-CpG甲基化主要出现在多能干细胞中，已经分化的细胞有所降低，特化的体细胞中几乎完全没有发现。2、虽然我们还没有发现non-CpG甲基化具有什么特定的功能，但是它在诱导iPS cell形成过程中得到重现。3、在不同的干细胞类型中， 这种形式不保守具有较大的可变性。4、non-CpG甲基化程度和DNA甲基化转移酶（DNMT3）的表达量具有强相关性，为了证明这种关系，在hESCs中，敲除DNMT3A和DNMT3B后，non-CpG甲基化程度整体下降。5、作者还发现，non-CpG甲基化与CpG甲基化相关。本研究为将来揭示胞嘧啶甲基化模式奠定了一定基础，为探索全基因组DNA甲基化分布提供了一个新的模式，为解决多能干细胞研究中面临的问题提供了一种新的思路。

Abstract

DNA methylation plays an important role in development and disease. The primary sites of DNA methylation in vertebrates are cytosines in the CpG dinucleotide context, which account for roughly three quarters of the total DNA methylation content in human and mouse cells. While the genomic distribution, inter-individual stability, and functional role of CpG methylation are reasonably well understood, little is known about DNA methylation targeting CpA, CpT, and CpC (non-CpG) dinucleotides. Here we report a comprehensive analysis of non-CpG methylation in 76 genome-scale DNA methylation maps across pluripotent and differentiated human cell types. We confirm non-CpG methylation to be predominantly present in pluripotent cell types and observe a decrease upon differentiation and near complete absence in various somatic cell types. Although no function has been assigned to it in pluripotency, our data highlight that non-CpG methylation patterns reappear upon iPS cell reprogramming. Intriguingly, the patterns are highly variable and show little conservation between different pluripotent cell lines. We find a strong correlation of non-CpG methylation and DNMT3 expression levels while showing statistical independence of non-CpG methylation from pluripotency associated gene expression. In line with these findings, we show that knockdown of DNMTA and DNMT3B in hESCs results in a global reduction of non-CpG methylation. Finally, non-CpG methylation appears to be spatially correlated with CpG methylation. In summary these results contribute further to our understanding of cytosine methylation patterns in human cells using a large representative sample set.

原文：Genomic Distribution and Inter-Sample Variation of Non-CpG Methylation across Human Cell Types. PLoS Genet, 2011, 7(12): 1-15.

编辑: gaowei2010

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