Genomic Functional Analysis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Comput Biol. 2019 Jul 22;15(7):e1007095. doi: 10.1371/journal.pcbi.1007095. eCollection 2019 Jul.
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.
替代转录异构体在肿瘤中很常见，它们可能是癌症的驱动因素。决定改变的异构体表达的机制包括剪接调节部位的体细胞突变或改变的剪接因子。然而，由于已知 DNA 甲基化可调节正常细胞中转录异构体的活性，我们预测在癌症中存在高度失调的 DNA 甲基化模式也会影响异构体的活性。我们分析了来自 18 种人类癌症类型的 DNA 甲基化和 RNA-seq 异构体数据，发现了 11 种癌症类型中存在的频繁相关性。检查变异甲基化位点的前 25%，发现基因中甲基化 CpG 位点的位置决定了使用哪个异构体。此外，相关的甲基化-异构体模式将肿瘤分为已知亚型，并预测了肿瘤亚型之间的不同蛋白质功能。最后，与甲基化相关的异构体富含致癌基因、肿瘤抑制基因和癌症相关途径。这些发现为失调的 DNA 甲基化在癌症中的功能影响提供了新的见解，并强调了表观基因组和转录组之间的关系。
