Genome-wide profiling of promoter methylation in human
Genome-wide profiling of promoter methylation in human
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DOI：
10.1038/sj.onc.1209331
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发表时间：
2006-05-18
期刊：
影响因子：
8
通讯作者：
Sasaki, H.
中科院分区：
文献类型：
--
作者：
Hatada, I.;Fukasawa, M.;Sasaki, H.
基因启动子区域的DNA甲基化与该基因表达的丧失相关，并且在基因沉默中起重要作用。在肿瘤发生过程中，启动子区异常甲基化导致的抑癌基因失活是公认的。然而，当涉及到启动子甲基化的全基因组分析时，在这一领域的研究很少。在这里，我们开发了一种全基因组分析方法，称为基于微阵列的异构体甲基化综合分析，以分析8091个人类基因启动子区域的DNA甲基化。用这种方法，通过使用具有8091个基因的启动子区域的微阵列，在样品之间比较对甲基化敏感的限制性内切酶HpaII和甲基化不敏感的异构体MspI的抗性。利用MspI抗性的差异判断HpaII抗性差异的可靠性。我们通过发现癌症中的表观遗传突变证明了这种方法的实用性。已知异常的甲基化可抑制肿瘤抑制基因。使用这种方法，我们发现癌症中异常启动子超甲基化的频率高于先前的假设。已知异常低甲基化可诱导癌症中癌基因的激活。对癌症中低甲基化启动子序列的全基因组分析表明，这些序列的CG/GC比率较低，表明CpG贫乏基因对癌症中的去甲基化活性敏感。
DNA methylation in the promoter region of a gene is associated with a loss of that gene's expression and plays an important role in gene silencing. The inactivation of tumor-suppressor genes by aberrant methylation in the promoter region is well recognized in carcinogenesis. However, there has been little study in this area when it comes to genome-wide profiling of the promoter methylation. Here, we developed a genome-wide profiling method called Microarray-based Integrated Analysis of Methylation by Isoschizomers to analyse the DNA methylation of promoter regions of 8091 human genes. With this method, resistance to both the methylation-sensitive restriction enzyme HpaII and the methylation-insensitive isoschizomer MspI was compared between samples by using a microarray with promoter regions of the 8091 genes. The reliability of the difference in HpaII resistance was judged using the difference in MspI resistance. We demonstrated the utility of this method by finding epigenetic mutations in cancer. Aberrant hypermethylation is known to inactivate tumour suppressor genes. Using this method, we found that frequency of the aberrant promoter hypermethylation in cancer is higher than previously hypothesized. Aberrant hypomethylation is known to induce activation of oncogenes in cancer. Genome-wide analysis of hypomethylated promoter sequences in cancer demonstrated low CG/GC ratio of these sequences, suggesting that CpG-poor genes are sensitive to demethylation activity in cancer.