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Histone modification (H3K4me3, H3K27ac, and H3K27me3) change during EBV infection in gastric epithelial cells

ABSTRACT: Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer, and Epstein-Barr virus (EBV) positive gastric cancer is known as the most frequently hypermethylated tumor among whole human malignancies. We here performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration. While 7,727 genes showed increase of DNA methylation in a promoter region, roughly half of these were “DNA methylation-sensitive” genes including anti-oncogenic genes e.g. CDKN2A and CDH1, which acquired DNA methylation in the whole promoter regions, thus leading to gene repression. Another half were “DNA methylation-resistant” genes including DNA repair genes, where DNA methylation is acquired in the surrounding of promoter regions but unmethylated status is protected in the vicinity of transcription start site, with gene expression retained. Histone modification alteration also occurred dynamically during EBV infection, in coordinated manner with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks e.g. H3K4me3 and H3K27ac, and apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes, and genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Orchestrated epigenetic alterations play an important role in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at TSS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97837 | GEO | 2017/08/21

SECONDARY ACCESSION(S): PRJNA382993

REPOSITORIES: GEO

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Project description:Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with neuroendocrine features. Although the role of epigenetic in tumorigenesis has been documented in most type of cancer, it is overlooked in MCC. The treatment options for MCC is limited and the five-year survival rate remains as low as 33%. In addition, recent studies have suggested multiple mechanisms of epigenetic dysregulation that may contribute to loss H3K27me3 and the tumorigenesis in MCC but not well studied. In this study, we conducted DNA methylation analysis of an existing retrospective cohort of clinically annotated MCC samples, which included samples from 8 primary tumors, three metastatic skin tumors, four metastatic lymph node tumors, and five paired normal tissue samples. Global DNA methylation profile was performed using Illumina Infinium MethylationEPIC array. Two MCC cell lines were also analyzed for DNA methylation and gene expression (RNA-seq) to confirm the correlation between DNA methylation and gene expression for MCC. Our analysis revealed 24,497 loci (14,456 genes) that showed significantly different DNA methylation pattern in the four groups (ANOVA p-value < 0.05 and standard deviation of mean of groups > 0.25) namely adjacent normal, primary tumor, metastatic skin, and metastatic lymph node in MCC patients. By GO terms analysis, the genes correlated with DNA methylation alteration associated with nervous system, cell adhesion, signal transduction, and development pathways. We also observed 870 probes differentially methylated in MCPyV positive and MCPyV negative tumor (FDR adjusted p-value < 0.05 and delta change greater than 0.4 or less than -0.4). Furthermore, using expression and DNA methylation data from two MCC cell lines (MS1 and MCC13) as validation, we identified 964 MCC specific genes directly regulated by DNA methylation either at promoter or gene body, which are highly enriched in nervous system related pathways. By this approach, we not only identify DNA methylation markers for MCC and MCPyV status but also genes regulated by DNA methylation in MCC, MCPyV status, and neuroendocrine features. Most importantly, our results may also suggest overexpression of KDM6B and EZHIP by loss of DNA methylation in their promoter may contribute to loss of H3K27me3 in MCC. In addition, we observed the DNA methylation profile of MS1 resembled MCC patient sample, while DNA methylation profile of MCC13 cell line was similar to small cell lung carcinoma (SCLC), which suggested that MCC13 cell line may originally come from SCLC. Taken together, we have demonstrated dramatic DNA methylation alteration along with four unique patterns in normal, primary and metastatic MCC. Our finding provides DNA methylation markers not only for diagnosis or prognosis of MCC and MCPyV status but also correlate gene expression status of MCC specific genes with important functional roles in MCC tumorigenesis, MCPyV expression, neuroendocrine feature and H3K27me3 status. The identification of DNA methylation alteration in MCC also provides foundation for potential implication of epigenetic therapy for MCC patients.

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Histone modification (H3K4me3, H3K27ac, and H3K27me3) change during EBV infection in gastric epithelial cells

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