Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
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DOI：
10.1038/s41467-019-09937-w
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发表时间：
2019-05-16
影响因子：
16.6
通讯作者：
Califano, Joseph A.
中科院分区：
文献类型：
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作者：
Ando, Mizuo;Saito, Yuki;Califano, Joseph A.
虽然启动子相关的CpG岛已被确定为癌症中DNA甲基化变化的靶点，但先前的研究表明，启动子区域外的表观遗传失调可能与转录变化更密切相关。在这里，我们检查DNA甲基化，染色质标记，和转录改变，以确定转录调节和染色质结构的空间变化之间的关系。使用人乳头瘤病毒相关口咽癌作为模型，我们显示了抑制性H3 K9 me 3在转录起始位点（TSS）的异常富集与甲基化相关的肿瘤特异性基因沉默。进一步的分析鉴定了一种高甲基化亚型，其显示了对MYC靶点的功能收敛并与CREBBP/EP 300突变相关。在多种肿瘤类型中证实了与TSS处的DNA甲基化相关的肿瘤特异性转录抑制转变。我们的数据可能显示了癌症中常见的潜在表观遗传失调，与抑制性染色质标记的广泛富集和TSS处的异常DNA超甲基化以及MYC网络激活相关。
Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.