Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, 08826, Korea.
Department of Computer Science and Engineering, Seoul National University, Seoul, 08826, Korea.
BMC Med Genomics. 2020 Feb 24;13(Suppl 3):27. doi: 10.1186/s12920-020-0659-4.
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.
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.
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.
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.
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至关重要，这导致了包括肿瘤抑制基因在内的重要基因的激活或抑制。表观遗传修饰物的突变会影响酶的活性，从而导致全基因组甲基化谱的差异和下游基因的激活。因此，我们通过泛癌症分析研究了 DNA 甲基化修饰基因（如 DNMT1、DNMT3A、MBD1、MBD4、TET1、TET2 和 TET3）的突变对其的影响。
首先，我们研究了 DNA 甲基化修饰基因的突变对全基因组甲基化谱的影响。我们从癌症基因组图谱（TCGA）中的 12 种主要癌症类型中收集了 3644 个既有 mRNA 又有甲基化数据的样本。根据突变特征，将样本分为两组。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 的结果，我们构建了一个在泛癌症范围内的综合 DNA 甲基化图谱。其次，我们比较了 11 种癌症类型中两组样本的启动子区 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 DEGs 中，我们使用基于图的子网络聚类方法选择了具有差异甲基化启动子的高度相关基因集。
我们选择了一个上调的 DEGs 聚类，其中急性髓系白血病（LAML）的启动子呈低甲基化，另一个下调的 DEGs 聚类，其中结肠腺癌（COAD）的启动子呈高甲基化。为了排除转录因子（TF）对基因调控的影响，如果差异表达的 TF 结合到 DEGs 的启动子上，那么这些 DEGs 就不会被包含在受 DNA 甲基化修饰物影响的基因集中。因此，我们在 LAML 中鉴定了 54 个低甲基化启动子 DMR 上调的 DEGs 和 45 个高甲基化启动子 DMR 下调的 COAD 下调的 DEGs。
我们对突变与非突变组中的 DNA 甲基化修饰基因的研究可以为癌症中 DEGs 的表观遗传调控提供有用的见解。
