Epigenetic Alterations of Viral and Cellular Genomes in EBV-Infected Cells

Abstract

Epstein–Barr virus (EBV), a human herpesvirus, replicates in oropharyngeal epithelial cells and establishes latency in memory B cells. A series of neoplasms including lymphomas, carcinomas, and leiomyosarcomas also carry latent EBV genomes. The viral episomes are subject to epigenetic modifications, including DNA methylation, histone modifications, and formation of chromatin loops in various host cells. These epigenetic alterations control the host cell-dependent activity of latent EBV promoters. Viral methylomes, i.e., the CpG methylation patterns of the latent episomes, also vary, depending on the host cell phenotype. Although there are distinct, invariably unmethylated regions in EBV genomes, like sequences within oriP, the latent origin of EBV replication, the overall level methylation of the viral episomes is high in Burkitt’s lymphomas (BLs) and nasopharyngeal carcinomas (NPCs), whereas lymphoblastoid cell lines (LCLs) carry hypomethylated viral genomes. Latency products, including nuclear and transmembrane proteins expressed in EBV-infected cells, interact either directly or indirectly with the epigenetic machinery of the host cell and may modify its epigenotype and gene expression pattern. Such epigenetic alterations may play a role in the development of EBV-associated neoplasms. Recently, the methylomes of EBV-positive BLs, NPCs, and EBV-associated gastric carcinomas (EBVaGCs) were thoroughly analyzed. These tumors exhibited a CpG island methylator phenotype (CIMP) characterized with a dysregulation of gene expression due to the silencing of key cellular promoters. In contrast, a complete genomic bisulfite sequence analysis of quiescent B cells and in vitro EBV-infected B lymphoblasts revealed a profound, genome-wide demethylation suggesting that the epigenetic events associated with B-cell immortalization, a possible counterpart of the development of posttransplant lymphoproliferative disease (PTLD), differ from the epigenetic dysregulation observed in BLs, NPCs, and EBVaGCs.