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Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
Nature Communications ( IF 14.7 ) Pub Date : 2019-04-15 , DOI: 10.1038/s41467-019-09828-0
Arie B Brinkman 1 , Serena Nik-Zainal 2, 3 , Femke Simmer 1, 4 , F Germán Rodríguez-González 5 , Marcel Smid 5 , Ludmil B Alexandrov 2, 6, 7 , Adam Butler 2 , Sancha Martin 2 , Helen Davies 2 , Dominik Glodzik 2 , Xueqing Zou 2 , Manasa Ramakrishna 2 , Johan Staaf 8 , Markus Ringnér 8 , Anieta Sieuwerts 5 , Anthony Ferrari 9 , Sandro Morganella 10 , Thomas Fleischer 11 , Vessela Kristensen 11, 12, 13 , Marta Gut 14 , Marc J van de Vijver 15 , Anne-Lise Børresen-Dale 11, 12 , Andrea L Richardson 16, 17 , Gilles Thomas 9 , Ivo G Gut 14 , John W M Martens 5 , John A Foekens 5 , Michael R Stratton 2 , Hendrik G Stunnenberg 1
Affiliation  

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.



中文翻译:


部分甲基化结构域在乳腺癌中高度可变,并促进广泛的 CpG 岛高甲基化



DNA 甲基化的整体缺失和 CpG 岛 (CGI) 超甲基化是癌症中关键的表观基因组畸变。全局丢失表现为部分甲基化域(PMD),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,以及它们对包括 CGI 在内的关键功能基因组元件的影响尚不清楚。我们全面表明 PMD 中甲基化的缺失发生在基因组的很大一部分中,并且代表了 DNA 甲基化变异的主要来源。 PMD 的甲基化水平、大小和分布高度可变,并表现出较高的突变率。它们强加中间 DNA 甲基化水平,但不识别包括 CGI 在内的功能基因组元件,从而支撑 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 的基因组分布报告了组织起源,并且可能代表组织特异性沉默区域,这些区域在表观遗传、转录组和遗传水平上耐受不稳定性。

更新日期:2019-05-16
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