BACKGROUND In cancer, mutations of DNA methylation modification genes have crucial roles for epigenetic modifications genome-wide, which lead to the activation or suppression of important genes including tumor suppressor genes. Mutations on the epigenetic modifiers could affect the enzyme activity, which would result in the difference in genome-wide methylation profiles and, activation of downstream genes. Therefore, we investigated the effect of mutations on DNA methylation modification genes such as DNMT1, DNMT3A, MBD1, MBD4, TET1, TET2 and TET3 through a pan-cancer analysis. METHODS First, we investigated the effect of mutations in DNA methylation modification genes on genome-wide methylation profiles. We collected 3,644 samples that have both of mRNA and methylation data from 12 major cancer types in The Cancer Genome Atlas (TCGA). The samples were divided into two groups according to the mutational signature. Differentially methylated regions (DMR) that overlapped with the promoter region were selected using minfi and differentially expressed genes (DEG) were identified using EBSeq. By integrating the DMR and DEG results, we constructed a comprehensive DNA methylome profiles on a pan-cancer scale. Second, we investigated the effect of DNA methylations in the promoter regions on downstream genes by comparing the two groups of samples in 11 cancer types. To investigate the effects of promoter methylation on downstream gene activations, we performed clustering analysis of DEGs. Among the DEGs, we selected highly correlated gene set that had differentially methylated promoter regions using graph based sub-network clustering methods. RESULTS We chose an up-regulated DEGs cluster where had hypomethylated promoter in acute myeloid leukemia (LAML) and another down-regulated DEGs cluster where had hypermethylated promoter in colon adenocarcinoma (COAD). To rule out effects of gene regulation by transcription factor (TF), if differentially expressed TFs bound to the promoter of DEGs, that DEGs did not included to the gene set that effected by DNA methylation modifiers. Consequently, we identified 54 hypomethylated promoter DMR up-regulated DEGs in LAML and 45 hypermethylated promoter DMR down-regulated DEGs in COAD. CONCLUSIONS Our study on DNA methylation modification genes in mutated vs. non-mutated groups could provide useful insight into the epigenetic regulation of DEGs in cancer.

中文翻译：

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DNA甲基化修饰基因中的突变对全基因组全甲基化景观和下游基因激活的影响。

背景技术在癌症中，DNA甲基化修饰基因的突变对于全基因组的表观遗传修饰具有关键作用，其导致重要基因的激活或抑制，包括肿瘤抑制基因。表观遗传修饰子上的突变可能影响酶的活性，这将导致全基因组甲基化谱的差异以及下游基因的激活。因此，我们通过泛癌分析研究了突变对DNA甲基化修饰基因（例如DNMT1，DNMT3A，MBD1，MBD4，TET1，TET2和TET3）的影响。方法首先，我们研究了DNA甲基化修饰基因中的突变对全基因组甲基化谱的影响。我们在《癌症基因组图集》（TCGA）中收集了3,644个样本，其中包含来自12种主要癌症类型的mRNA和甲基化数据。根据突变特征将样品分为两组。使用minfi选择与启动子区域重叠的差异甲基化区域（DMR），并使用EBSeq鉴定差异表达基因（DEG）。通过整合DMR和DEG结果，我们在全癌规模上构建了全面的DNA甲基化基因组图谱。其次，我们通过比较11种癌症类型的两组样本，研究了启动子区域DNA甲基化对下游基因的影响。为了研究启动子甲基化对下游基因激活的影响，我们对DEGs进行了聚类分析。在DEG中，我们使用基于图的子网聚类方法选择了具有差异甲基化启动子区域的高度相关的基因集。结果我们选择了上调的DEGs簇，其中在急性髓性白血病（LAML）中具有低甲基化启动子，而另一个下调的DEGs簇，在结肠腺癌（COAD）中具有高甲基化启动子。为了排除由转录因子（TF）调控基因的影响，如果差异表达的TF与DEGs的启动子结合，则该DEGs不包括在受DNA甲基化修饰剂影响的基因组中。因此，我们在LAML中鉴定了54个甲基化过低的启动子DMR上调了DEG，在COAD中鉴定了45个甲基化过高的启动子DMR上调了DEG。结论我们对突变组和非突变组中DNA甲基化修饰基因的研究可以为癌症DEGs的表观遗传调控提供有用的见识。