Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer
Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer
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DOI：
10.1111/cas.13937
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发表时间：
2019-03-01
期刊：
影响因子：
5.7
通讯作者：
Kawazu, Masahito
中科院分区：
文献类型：
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作者：
Namba, Shinichi;Sato, Kazuhito;Kawazu, Masahito
启动子CpG岛（CGI）甲基化导致抑癌基因沉默是肿瘤发生的重要原因。MLH 1和BRCA 1的沉默是致癌事件的两个例子，由启动子CGI甲基化引起。有趣的是，MLH 1和BRCA 1都有一个不同的启动子，另一个基因也从相反的链转录。尽管研究表明趋异转录是转录调控中的一个重要因素，但对其在癌症中异常启动子甲基化中的意义知之甚少。在这项研究中，我们分析了CGI的甲基化状态，在不同的启动子使用最近丰富的转录组数据库。我们使用Infinium MethylationEPIC BeadChip检测了119例结直肠癌（CRC）临床样本（65例微卫星不稳定性高[MSI-H] CRC伴CGI甲基化表型，28例MSI-H CRC不伴CGI甲基化表型，26例微卫星稳定CRC）和21例正常结直肠组织中CGI甲基化的程度。我们发现，在正常细胞中，趋异启动子内的CGI甲基化频率低于单向启动子内的CGI。在CRC细胞的基因组中，单向启动子内的CGI比趋异启动子内的CGI更容易发生异常甲基化。此外，我们确定了三个与甲基化CGI相关的DNA序列基序。我们还发现，甲基化CGI与正常细胞中低表达的基因相关。因此，我们在这里提供了关于不同启动子甲基化的基本观察，这些甲基化对于理解癌症发生和癌症预防策略的发展至关重要。
The silencing of tumor suppressor genes by promoter CpG island (CGI) methylation is an important cause of oncogenesis. Silencing of MLH1 and BRCA1, two examples of oncogenic events, results from promoter CGI methylation. Interestingly, both MLH1 and BRCA1 have a divergent promoter, from which another gene on the opposite strand is also transcribed. Although studies have shown that divergent transcription is an important factor in transcriptional regulation, little is known about its implication in aberrant promoter methylation in cancer. In this study, we analyzed the methylation status of CGI in divergent promoters using a recently enriched transcriptome database. We measured the extent of CGI methylation in 119 colorectal cancer (CRC) clinical samples (65 microsatellite instability high [MSI-H] CRC with CGI methylator phenotype, 28 MSI-H CRC without CGI methylator phenotype and 26 microsatellite stable CRC) and 21 normal colorectal tissues using Infinium MethylationEPIC BeadChip. We found that CGI within divergent promoters are less frequently methylated than CGI within unidirectional promoters in normal cells. In the genome of CRC cells, CGI within unidirectional promoters are more vulnerable to aberrant methylation than CGI within divergent promoters. In addition, we identified three DNA sequence motifs that correlate with methylated CGI. We also showed that methylated CGI are associated with genes whose expression is low in normal cells. Thus, we here provide fundamental observations regarding the methylation of divergent promoters that are essential for the understanding of carcinogenesis and development of cancer prevention strategies.