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Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.

ABSTRACT: 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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7021546 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.

Wang Zhihui Z Du Mulong M Yuan Qianyu Q Guo Yichen Y Hutchinson John N JN Su Li L Zheng Yinan Y Wang Jun J Mucci Lorelei A LA Lin Xihong X Hou Lifang L Christiani David C DC

Neoplasia (New York, N.Y.) 20200212 3

<h4>Background</h4>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.<h4>Methods</h4>We analyzed the epigenome-wide 5hmC profiles of paired lung tumor and adjacent normal tissues, using the TET-Assisted Bisulfite (TAB) array - Infinium MethylationEPIC Bea ...[more]

PMID: 32062069

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Project description:Background: Aberrant DNA methylation occurs commonly during carcinogenesis and is of clinical value in human cancers. However, knowledge of the impact of DNA methylation changes on lung carcinogenesis and progression remains limited. Methods: Genome-wide DNA methylation profiles were surveyed in 18 pairs of tumors and adjacent normal tissues from non-small cell lung cancer (NSCLC) patients using Reduced Representation Bisulfite Sequencing (RRBS). An integrated epigenomic-transcriptomic landscape of lung cancer was depicted using the multi-omics data integration method. Results: We discovered a large number of hypermethylation events pre-marked by poised promoter in embryonic stem cells, being a hallmark of lung cancer. These hypermethylation events showed a high conservation across cancer types. Eight novel driver genes with aberrant methylation (e.g., PCDH17 and IRX1) were identified by integrated analysis of DNA methylome and transcriptome data. Methylation level of the eight genes measured by pyrosequencing can distinguish NSCLC patients from lung tissues with high sensitivity and specificity in an independent cohort. Their tumor-suppressive roles were further experimentally validated in lung cancer cells, which depend on promoter hypermethylation. Similarly, 13 methylation-driven ncRNAs (including 8 lncRNAs and 5 miRNAs) were identified, some of which were co-regulated with their host genes by the same promoter hypermethylation. Finally, by analyzing the transcription factor (TF) binding motifs, we uncovered sets of TFs driving the expression of epigenetically regulated genes and highlighted the epigenetic regulation of gene expression of TCF21 through DNA methylation of EGR1 binding motifs. Conclusions: We discovered several novel methylation driver genes of diagnostic and therapeutic relevance in lung cancer. Our findings revealed that DNA methylation in TF binding motifs regulates target gene expression by affecting the binding ability of TFs. Our study also provides a valuable epigenetic resource for identifying DNA methylation-based diagnostic biomarkers, developing cancer drugs for epigenetic therapy and studying cancer pathogenesis.

Dataset Information

Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.

Publications

Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.

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