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Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets

机译:人类癌症基因组中全面的DNA甲基化图谱鉴定了新的表观遗传学靶标

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摘要

Using a unique microarray platform for cytosine methylation profiling, the DNA methylation landscape of the human genome was monitored at more than 21,000 sites, including 79% of the annotated transcriptional start sites (TSS). Analysis of an oligodendroglioma derived cell line LN-18 revealed more than 4000 methylated TSS. The gene-centric analysis indicated a complex pattern of DNA methylation exists along each autosome, with a trend of increasing density approaching the telomeres. Remarkably, 2% of CpG islands (CGI) were densely methylated, and 17% had significant levels of 5 mC, whether or not they corresponded to a TSS. Substantial independent verification, obtained from 95 loci, suggested that this approach is capable of large scale detection of cytosine methylation with an accuracy approaching 90%. In addition, we detected large genomic domains that are also susceptible to DNA methylation reinforced inactivation, such as the HOX cluster on chromosome 7 (CH7). Extrapolation from the data suggests that more than 2000 genomic loci may be susceptible to methylation and associated inactivation, and most have yet to be identified. Finally, we report six new targets of epigenetic inactivation (IRX3, WNT10A, WNT6, RARalpha, BMP7 and ZGPAT). These targets displayed cell line and tumor specific differential methylation when compared with normal brain samples, suggesting they may have utility as biomarkers. Uniquely, hypermethylation of the CGI within an IRX3 exon was correlated with over-expression of IRX3 in tumor tissues and cell lines relative to normal brain samples.
机译:使用用于胞嘧啶甲基化分析的独特微阵列平台,在超过21,000个位点(包括79%的带注释的转录起始位点(TSS))上监测了人类基因组的DNA甲基化态势。对源自少突胶质细胞瘤的细胞系LN-18的分析显示,有4000多种甲基化的TSS。以基因为中心的分析表明,每个常染色体都存在复杂的DNA甲基化模式,并且趋向于端粒密度增加。值得注意的是,有2%的CpG岛(CGI)被密集地甲基化,而17%的显着水平为5 mC,无论它们是否对应于TSS。从95个位点获得的大量独立验证表明,该方法能够大规模检测胞嘧啶甲基化,准确度接近90%。此外,我们检测到了大型基因组域,它们也容易受到DNA甲基化增强失活的影响,例如7号染色体上的HOX簇(CH7)。根据数据推断,可能有2000多个基因组位点易发生甲基化和相关的失活,而且大多数尚未被确定。最后,我们报告了表观遗传失活的六个新目标(IRX3,WNT10A,WNT6,RARalpha,BMP7和ZGPAT)。与正常脑样本相比,这些靶标显示细胞系和肿瘤特异性甲基化差异,表明它们可能具有生物标志物的作用。独特的是,IRX3外显子内CGI的甲基化与肿瘤组织和细胞系中相对于正常脑样本的IRX3过表达有关。

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