5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

摘要: Latent Epstein–Barr virus (EBV) infection and cellular hypermethylation are hallmarks of undifferentiated nasopharyngeal carcinoma (NPC). However, EBV normal oral epithelial cells is confined to differentiated lytic. Here we demonstrate that the genome can become 5-hydroxymethylated this DNA modification affects lytic reactivation. We show global 5-hydroxymethylcytosine (5hmC)-modified accumulates during epithelial-cell differentiation, whereas EBV+ NPCs have little if any 5hmC-modified DNA. Furthermore, find increasing ten–eleven translocation (TET) activity [which converts methylated cytosine (5mC) 5hmC] decreases methylation, increases 5hmC modification, promoters in EBV-infected cell lines containing highly viral genomes. Conversely, inhibition endogenous TET promoter methylation an telomerase-immortalized keratinocyte (NOKs) line where largely unmethylated. these modifications differentially affect ability two immediate-early proteins, BZLF1 (Z) BRLF1 (R), induce form infection. Although Z-mediated inhibits R-mediated reactivation, has opposite effect. also identify a specific CpG-containing Z-binding site on must be for reactivation TET-mediated NOKs prevents Decreased 5-hydroxymethylation genes may contribute NPC formation.