Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries
Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries
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DOI：
10.3892/ijmm_00000515
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Zaina, Silvio
中科院分区：
文献类型：
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作者：
Castillo-Diaz, Silvia A.;Garay-Sevilla, Maria E.;Zaina, Silvio
在动脉粥样硬化病变中，可能导致致动脉粥样硬化基因表达的DNA低甲基化。然而，关于低甲基化序列的基因组位置的信息有限。我们提出了一个基于微阵列的调查CpG岛（CGIs）的甲基化状态在45人动脉粥样硬化动脉和16个对照。来自10，367个CGI的数据显示，其中一个子集（151或1.4%）在对照动脉中是高甲基化的。绝大多数（142或94%）的CGI子集被发现是未甲基化或部分甲基化的动脉粥样硬化组织中，而只有17个正常的未甲基化的CGI是高甲基化的病变组织。最常见的功能类注释基因相邻或含有差异甲基化的CGIs，转录（23%）和信号传导因子（16%）。前者包括HOX成员，PROXI，NOTCHI和FOXPI，已知它们调节动脉粥样硬化形成的关键步骤。表达分析显示所有CGI相关基因的差异表达分析。序列分析确定了具有调控潜力的新DNA基序，与差异甲基化CGIs相关。这项研究是第一次大规模分析动脉粥样硬化中的DNA甲基化。我们的数据表明，动脉粥样硬化中异常的DNA甲基化影响了诱导促动脉粥样硬化细胞表型的关键调控基因的转录。
Global DNA hypomethylation potentially leading to pro-atherogenic gene expression occurs in atherosclerotic lesions. However, limited information is available on the genomic location of hypomethylated sequences. We present a microarray-based survey of the methylation status of CpG islands (CGIs) in 45 human atherosclerotic arteries and 16 controls. Data from 10,367 CGIs revealed that a subset (151 or 1.4%) of these was hypermethylated in control arteries. The vast majority (142 or 94%) of this CGI subset was found to be unmethylated or partially methylated in atherosclerotic tissue, while only 17 of the normally unmethylated CGIs were hypermethylated in the diseased tissue. The most common functional classes among annotated genes adjacent to or containing differentially methylated CGIs, were transcription (23%) and signalling factors (16%). The former included HOX members, PROXI, NOTCHI and FOXPI, which are known to regulate key steps of atherogenesis. Expression analysis revealed differential expression of all CGI-associated genes analysed. Sequence analysis identified novel DNA motifs with regulatory potential, associated with differentially methylated CGIs. This study is the first large-scale analysis of DNA methylation in atherosclerosis. Our data suggest that aberrant DNA methylation in atherosclerosis affects the transcription of critical regulatory genes for the induction of a pro-atherogenic cellular phenotype.