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首页> 外文期刊>RSC Advances >Determination of DNA adenine methylation in genomes of mammals and plants by liquid chromatography/mass spectrometry
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Determination of DNA adenine methylation in genomes of mammals and plants by liquid chromatography/mass spectrometry

机译：液相色谱/质谱法测定哺乳动物和植物基因组中的DNA腺嘌呤甲基化

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摘要

DNA adenine methylation (N-6-methyl-2'-deoxyadenosine, m(6)dA) plays important functional roles in prokaryotes and protists, including regulation of gene transcription, DNA replication and repair, and the restriction-modification system. However, there is no definitive evidence supporting the presence of DNA adenine methylation in genomic DNA of higher eukaryotes, such as mammals and plants, where DNA cytosine methylation (5-methylcytosine) instead is well recognized as an important epigenetic mark that has regulatory roles in various biological processes. In the current study, we developed a Dpn I cleavage coupled with size-exclusion ultrafiltration method, with which we discovered the wide-spread existence of m(6)dA in genomic DNA of higher eukaryotes, including human cells, rat tissues, and plants besides bacteria and protists by employing high-resolution mass spectrometry analysis. And the contents of m(6)dA vary in different cell types with the range of 0.00006-0.00077% (m(6)dA dA(-1)). Moreover, similar to N-6-methyladenosine (m(6)A) in RNA, m(6)dA contents significantly decreased in type 2 diabetes mellitus (T2DM) patients compared to control subjects, indicating m(6)dA plays important roles in the pathogenesis of T2DM as m(6)A. In addition, knockdown of cellular fat mass and obesity-associated (FTO) protein increased the m(6)dA content, while overexpression of cellular FTO decreased m(6)dA content in DNA, suggesting m(6)dA and m(6)A may share the same demethylase of FTO. The demonstration of the universal presence of DNA adenine methylation constitutes the first and essential step toward understanding of m(6)dA functions in higher eukaryotes.
机译：DNA腺嘌呤甲基化（N-6-甲基-2'-脱氧腺苷，m（6）dA）在原核生物和原生生物中起着重要的功能作用，包括基因转录的调控，DNA复制和修复以及限制性修饰系统。但是，没有确凿的证据支持在诸如哺乳动物和植物等高等真核生物的基因组DNA中存在DNA腺嘌呤甲基化，而DNA胞嘧啶甲基化（5-甲基胞嘧啶）被公认是重要的表观遗传标记，在各种生物过程。在当前的研究中，我们开发了Dpn I裂解结合尺寸排阻超滤方法，利用该方法我们发现m（6）dA在高等真核生物的基因组DNA中广泛存在，包括人类细胞，大鼠组织和植物除细菌和原生生物外，还采用高分辨率质谱分析。而且，m（6）dA的含量在不同的细胞类型中有所不同，范围为0.00006-0.00077％（m（6）dA dA（-1））。此外，类似于RNA中的N-6-甲基腺苷（m（6）A），与对照组相比，在2型糖尿病（T2DM）患者中m（6）dA含量显着降低，表明m（6）dA发挥了重要作用在T2DM的发病机制中表现为m（6）A。此外，敲除细胞脂肪和肥胖相关（FTO）蛋白会增加m（6）dA含量，而细胞FTO的过表达会降低DNA中的m（6）dA含量，提示m（6）dA和m（6）甲可能共享相同的FTO脱甲基酶。 DNA腺嘌呤甲基化的普遍存在的证明是迈向理解高等真核生物m（6）dA功能的第一步，也是必不可少的步骤。

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