Aberrant DNA methylation defines isoform usage in cancer, with functional implications
Aberrant DNA methylation defines isoform usage in cancer, with functional implications
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DOI：
10.1371/journal.pcbi.1007095
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发表时间：
2019-07-01
影响因子：
4.3
通讯作者：
Elnitski, Laura
中科院分区：
文献类型：
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作者：
Chen, Yun-Ching;Elnitski, Laura
选择性转录异构体在肿瘤中很常见，并作为癌症的潜在驱动因素。决定改变的同种型表达的机制包括剪接调控位点的体细胞突变或改变的剪接因子。然而，由于已知DNA甲基化调节正常细胞中的转录异构体活性，因此我们预测癌症中存在的DNA甲基化的高度失调模式也会影响异构体活性。我们分析了来自18种人类癌症类型的DNA甲基化和RNA-seq亚型数据，发现了11种癌症类型之间的频繁相关性。检查前25%的可变甲基化位点揭示了甲基化CpG位点在基因中的位置决定了使用哪种同种型。此外，相关的甲基化亚型模式将肿瘤分类为已知的亚型，并预测肿瘤亚型之间不同的蛋白质功能。最后，甲基化相关的异构体富集癌基因，肿瘤抑制因子，和癌症相关的途径。这些发现为癌症中DNA甲基化失调的功能影响提供了新的见解，并突出了表观基因组和转录组之间的关系。
Alternative transcript isoforms are common in tumors and act as potential drivers of cancer. Mechanisms determining altered isoform expression include somatic mutations in splice regulatory sites or altered splicing factors. However, since DNA methylation is known to regulate transcriptional isoform activity in normal cells, we predicted the highly dysregulated patterns of DNA methylation present in cancer also affect isoform activity. We analyzed DNA methylation and RNA-seq isoform data from 18 human cancer types and found frequent correlations specifically within 11 cancer types. Examining the top 25% of variable methylation sites revealed that the location of the methylated CpG site in a gene determined which isoform was used. In addition, the correlated methylation-isoform patterns classified tumors into known subtypes and predicted distinct protein functions between tumor subtypes. Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways. These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome.