Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
复制标题
DOI：
10.1038/s41467-019-09828-0
复制
发表时间：
2019-04-15
影响因子：
16.6
通讯作者：
Stunnenberg, Hendrik G.
中科院分区：
文献类型：
--
作者：
Brinkman, Arie B.;Nik-Zainal, Serena;Stunnenberg, Hendrik G.
DNA甲基化的整体丧失和CpG岛（CGI）超甲基化是癌症中关键的表观基因组畸变。全局丢失表现在部分甲基化结构域（PMD）中，其延伸至兆碱基。然而，PMD在肿瘤类型内和肿瘤类型之间的分布及其对关键功能基因组元件（包括CGIs）的影响尚不清楚。我们全面表明，PMD中的甲基化丢失发生在基因组的大部分中，并且代表了DNA甲基化变异的主要来源。PMD在甲基化水平、大小和分布方面高度可变，并且显示出升高的突变率。它们强加中间DNA甲基化水平，而不认识包括CGI在内的功能基因组元件，从而支持CGI甲基化表型（CIMP）。对肿瘤抑制基因的抑制作用可以忽略不计，因为它们通常被排除在PMD之外。PMD的基因组分布报告组织的起源，并可能代表组织特异性沉默区域容忍不稳定的表观遗传，转录组和遗传水平。
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.