A DNA methylation fingerprint of 1628 human samples
A DNA methylation fingerprint of 1628 human samples
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DOI：
10.1101/gr.119867.110
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发表时间：
2012-02-01
期刊：
影响因子：
7
通讯作者：
Esteller, Manel
中科院分区：
文献类型：
--
作者：
Fernandez, Agustin F.;Assenov, Yassen;Esteller, Manel
大多数表征 DNA 甲基化模式的研究仅限于有限数量的人类样本和病理条件下的特定基因组位点。在此，我们提出了一种折衷方案，对人类样本群体进行极其全面的研究，并在基因组水平上对 CpG 进行中等水平的分辨率。我们获得了 1628 个人类样本的 DNA 甲基化指纹，其中我们询问了 1505 个 CpG 位点。揭示的 DNA 甲基化模式表明，这种表观遗传标记对于组织类型定义和严格性至关重要，特别是在不在 CpG 岛内的转录起始位点周围。对于疾病，生成的 DNA 甲基化指纹显示，在肿瘤发生过程中，人类癌细胞经历了启动子 CpG 岛高甲基化的逐渐增加和非 CpG 岛启动子中 CpG 甲基化的丧失。尽管转化细胞中 DNA 甲基化破坏更为明显，但我们观察到其他常见的人类疾病，例如神经系统和自身免疫性疾病，也有其独特的 DNA 甲基化谱。最重要的是，我们提供了原理证明，证明所获得的 DNA 甲基化指纹可能有助于翻译目的，表明我们能够识别未知原发性癌症 (cups) 的肿瘤类型起源。因此，迄今为止报道的最大范围的样本、组织和疾病中鉴定的 DNA 甲基化模式构成了开发更高分辨率 DNA 甲基化图谱的基线，并提供了关于 CpG 甲基化对组织身份的贡献及其在最常见的人类疾病中的变化的重要线索。
Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and sternness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (cups). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.