组蛋白修饰分析 5-羟甲基胞嘧啶（5hmC）揭示肺癌新型 DNA 甲基化标志物。
Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.
机构信息
Harvard Graduate School of Arts and Sciences, Harvard University, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
出版信息
Neoplasia. 2020 Mar;22(3):154-161. doi: 10.1016/j.neo.2020.01.001. Epub 2020 Feb 12.
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.
背景
胞嘧啶第 5 位的 DNA 甲基化（5mC）是一种常见的表观遗传改变，影响多种细胞过程。近年来，5-羟甲基胞嘧啶（5hmC）作为 5mC 的氧化形式，作为肺癌诊断和生存的潜在生物标志物引起了广泛关注。
方法
我们使用 TET 辅助亚硫酸氢盐（TAB）阵列- Infinium 甲基化 EPIC BeadChip（EPIC）方法分析了配对的肺癌肿瘤和相邻正常组织的全基因组 5hmC 图谱。鉴定差异甲基化 CpG 位点，并通过差异甲基化区域（DMR）分析和基因集分析（GSA）评估 5hmC 的生物学相关性。
结果
我们观察到肿瘤组织与正常组织相比 5hmC 整体呈低甲基化，而 5hmC 高甲基化富集在 CpG 岛和基因上游。5hmC 与 5modC（总甲基化：5mC+5hmC）图谱的比较显示出低相关性，并且只有一小部分显著的 5hmC 基因座与显著的总甲基化基因座重叠。GSA 分析表明，5hmC 主要参与细胞过程、生物调节和代谢过程等生物学过程。
结论
这是第一项分析配对肺癌肿瘤和正常组织全基因组 5hmC 图谱的研究。我们观察到肺癌中 5hmC 整体低甲基化，而 5hmC 高甲基化富集在 CpG 岛和基因上游。我们发现全基因组 5hmC 水平与总甲基化不相关，并且 GSA 表明与 5modC 相比，5hmC 具有不同的生物学功能。总的来说，我们的研究结果表明 5hmC 作为肺癌的新型生物标志物具有潜力。
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