Identification of regulatory role of DNA methylation in colon cancer gene expression via systematic bioinformatics analysis.
Identification of regulatory role of DNA methylation in colon cancer gene expression via systematic bioinformatics analysis.
复制标题
通过系统生物信息学分析鉴定 DNA 甲基化在结肠癌基因表达中的调节作用
DOI：
10.1097/md.0000000000008487
复制
发表时间：
2017-11
期刊：
影响因子：
1.6
通讯作者：
Wang XM
中科院分区：
文献类型：
--
作者：
Yang Y;Chu FH;Xu WR;Sun JQ;Sun X;Ma XM;Yu MW;Yang GW;Wang XM
摘要结肠癌是由遗传和表观遗传变化累积而成。目前，结肠癌的DNA甲基化和基因表达谱尚不清楚。本文旨在系统地研究结肠癌的DNA甲基化和基因表达谱，获得可能受结肠癌甲基化改变调控的候选基因。数据从癌症基因组图谱数据库下载。通过COHCAP计算差异甲基化CpG位点（DMC）和差异甲基化区域（DMR）。通过DESeq 2鉴定差异表达基因（DEG）。加权基因共表达网络分析（WGCNA）软件包在R中用于WGCNA。收集275例结肠癌实体瘤组织和19例癌旁组织的资料。在肿瘤组和正常组中共鉴定出1828个DMC，包括1390个高甲基化和438个低甲基化CpG位点。共观察到789个DEG，包含435个上调基因和354个下调基因。结果显示，8对DMRs-DEG和95对DMCs-DEG具有显著相关性。此外，WGCNA中黄色和棕色模块的基因与肿瘤/正常状态显著相关，并且在过氧化物酶体增殖物激活受体信号通路、突触和神经活性配体-受体相互作用中显著富集。上述2个模块中的基因也显著富集在DMC或DMR相关基因中。具体而言，ADHFE 1，HAND 2和GNAO 1在结肠癌中高甲基化和下调，表明这些基因的低表达水平可能受DNA高甲基化调控。此外，这3个基因均参与了WGCNA的棕色模块，表明它们在结肠癌中起着重要作用。探讨DNA甲基化与基因表达的关系，有助于了解DNA甲基化改变对基因表达，尤其是基因共表达网络在结肠癌发生发展中的作用。ADHFE 1、HAND 2和GNAO 1等基因可能成为结肠癌诊断和治疗的潜在候选靶点。
Abstract Colon cancer arises from the accumulations of genetic and epigenetic changes. Currently, profiles of DNA methylation and gene expression of colon cancer have not been elucidated clearly. This articles aims to characterize the profile of DNA methylation and gene expression of colon cancer systemically, and acquire candidate genes potentially regulated by altered methylation for this disease. Data were downloaded from The Cancer Genome Atlas database. Differentially methylated CpG sites (DMCs) and differentially methylated regions (DMRs) were calculated via COHCAP. Differentially expressed genes (DEGs) were identified by DESeq2. Weighted gene co-expression network analysis (WGCNA) package in R was applied for WGCNA. Data of 275 solid tumor tissues and 19 adjacent tumor tissues of colon cancer were obtained. A total of 1828 DMCs, including 1390 hypermethylated and 438 hypomethylated CpG sites, were identified between tumor and normal groups. A total of 789 DEGs, containing 435 upregulated genes and 354 downregulated genes were observed. It revealed that 8 DMRs-DEGs and 95 DMCs-DEGs pairs were significantly correlated. Furthermore, genes of yellow and brown modules from WGCNA were significantly correlated with tumor/normal status, and significantly enriched in peroxisome proliferator activated receptor signaling pathway, glutamatergic synapse, and neuroactive ligand-receptor interaction. Genes in the above 2 modules were also significantly enriched in DMCs or DMRs-associated genes. Specifically, ADHFE1, HAND2, and GNAO1 were hypermethylated and downregulated in colon cancer, suggesting that the low expression levels of these genes may be regulated by DNA hypermethylation. In addition, the 3 genes were involved in brown module of WGCNA, indicating their important roles in colon cancer. The investigation of the relationship between DNA methylation and gene expression may help to understand the effect of DNA methylation alteration on genes expression, especially gene co-expression network in the development of colon cancer. Genes such as ADHFE1, HAND2, and GNAO1 may be served as potential candidates for diagnosis and therapy targets in colon cancer.