RRC ID 63402
Author Namba-Fukuyo H, Funata S, Matsusaka K, Fukuyo M, Rahmutulla B, Mano Y, Fukayama M, Aburatani H, Kaneda A.
Title TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection.
Journal Oncotarget
Abstract Extensive DNA methylation is observed in gastric cancer with Epstein-Barr virus (EBV) infection, and EBV infection is the cause to induce this extensive hypermethylaton phenotype in gastric epithelial cells. However, some 5' regions of genes do not undergo de novo methylation, despite the induction of methylation in surrounding regions, suggesting the existence of a resistance factor against DNA methylation acquisition. We conducted an RNA-seq analysis of gastric epithelial cells with and without EBV infection and found that TET family genes, especially TET2, were repressed by EBV infection at both mRNA and protein levels. TET2 was found to be downregulated by EBV transcripts, e.g. BARF0 and LMP2A, and also by seven human miRNAs targeting TET2, e.g., miR-93 and miR-29a, which were upregulated by EBV infection, and transfection of which into gastric cells repressed TET2. Hydroxymethylation target genes by TET2 were detected by hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) with and without TET2 overexpression, and overlapped significantly with methylation target genes in EBV-infected cells. When TET2 was knocked down by shRNA, EBV infection induced de novo methylation more severely, including even higher methylation in methylation-acquired promoters or de novo methylation acquisition in methylation-protected promoters, leading to gene repression. TET2 knockdown alone without EBV infection did not induce de novo DNA methylation. These data suggested that TET2 functions as a resistance factor against DNA methylation in gastric epithelial cells and repression of TET2 contributes to DNA methylation acquisition during EBV infection.
Volume 7(49)
Pages 81512-81526
Published 2016-12-6
DOI 10.18632/oncotarget.13130
PII 13130
PMID 27829228
PMC PMC5348409
MeSH Cell Line, Tumor Cell Transformation, Viral* DNA Methylation* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Dioxygenases Epstein-Barr Virus Infections / genetics Epstein-Barr Virus Infections / metabolism Epstein-Barr Virus Infections / virology* Gastric Mucosa / metabolism Gastric Mucosa / virology* Gene Expression Regulation, Neoplastic Gene Expression Regulation, Viral Herpesvirus 4, Human / genetics Herpesvirus 4, Human / metabolism Herpesvirus 4, Human / pathogenicity* Host-Pathogen Interactions Humans MicroRNAs / genetics MicroRNAs / metabolism Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* RNA Interference RNA, Messenger / genetics RNA, Messenger / metabolism Stomach Neoplasms / genetics Stomach Neoplasms / metabolism Stomach Neoplasms / virology* Time Factors Transcription, Genetic Transcriptome Transfection Viral Matrix Proteins / genetics Viral Matrix Proteins / metabolism
IF 5.168
Human and Animal Cells MKN7(RCB0999)