BACKGROUND DNA methylation at the fifth position of cytosine (5mC) is a common epigenetic alteration affecting a range of cellular processes. In recent years, 5-hydroxymethylcytosine (5hmC), an oxidized form of 5mC, has risen broad interests as a potential biomarker for lung cancer diagnosis and survival. METHODS We analyzed the epigenome-wide 5hmC profiles of paired lung tumor and adjacent normal tissues, using the TET-Assisted Bisulfite (TAB) array - Infinium MethylationEPIC BeadChip (EPIC) approach. The differentially methylated CpG sites were identified, and the biological relevance of 5hmC was assessed by differential methylation regions (DMR) analysis and gene set analysis (GSA). RESULTS We observed global hypomethylation of 5hmC comparing tumor to normal tissues, and hypermethylated 5hmC were enriched in CpG islands and gene upstream. Comparison of 5hmC and 5modC (total methylation: 5mC + 5hmC) profiling showed low correlation, and only a small proportion of the significant 5hmC loci overlapped with the significant total methylation loci. GSA analysis suggested that 5hmC was mainly involved in biological processes such as cellular process, biological regulation, and metabolic process. CONCLUSION This is the first study to analyze the epigenome-wide 5hmC profiles among paired lung tumor and normal tissues. We observed global hypomethylation of 5hmC in lung cancers, and hypermethylated 5hmC enriched in CpG islands and gene upstream. We found that the genome-wide 5hmC levels do not correlate with the total methylation, and the GSA suggested different biological functions of 5hmC compared to 5modC. Overall, our results demonstrate the potential of 5hmC as a novel biomarker for lung cancer.

中文翻译：

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对5-羟甲基胞嘧啶（5hmC）的表观基因组学分析揭示了肺癌的新型DNA甲基化标记。

背景技术胞嘧啶（5mC）第五个位置的DNA甲基化是影响一系列细胞过程的常见表观遗传学改变。近年来，作为5mC的氧化形式的5-羟甲基胞嘧啶（5hmC）作为肺癌诊断和生存的潜在生物标记物已引起广泛关注。方法我们使用TET辅助的亚硫酸氢盐（TAB）阵列-甲基甲基化EPIC珠芯片（EPIC）方法分析了成对的肺肿瘤和邻近的正常组织的整个表观基因组5hmC谱。确定了差异甲基化的CpG位点，并通过差异甲基化区域（DMR）分析和基因组分析（GSA）评估了5hmC的生物学相关性。结果我们观察到5hmC的整体低甲基化，与正常组织相比，甲基化的5hmC在CpG岛和基因上游富集。5hmC和5modC（总甲基化：5mC + 5hmC）分析的比较显示出较低的相关性，只有一小部分显着的5hmC位点与显着的总甲基化位点重叠。GSA分析表明5hmC主要参与生物过程，例如细胞过程，生物调节和代谢过程。结论这是第一项分析配对肺肿瘤和正常组织中表观基因组范围内5hmC谱的研究。我们在肺癌中观察到了5hmC的整体低甲基化，并在CpG岛和基因上游富集了高度甲基化的5hmC。我们发现全基因组5hmC水平与总甲基化不相关，并且GSA建议与5modC相比5hmC具有不同的生物学功能。总体，