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Background  Epstein-Barr virus (EBV) establishes its latency in EBV-associated malignancies, accompanied by occasionally reactivated lytic cycle. Promoter CpG methylation of EBV genome plays an essential role in maintaining viral latency. Two immediate-early (IE) genes, BZLF1 and BRLF1, induce the switch from latent to lytic infection. Studies of methylation-dependent binding of BZLF1 and BRLF1 to EBV promoters have been well reported, but little is known about the methylation status of  BZLF1  and  BRLF1  promoters (Zp and Rp) in tumor samples.    Methods  We evaluated the methylation profiles of Zp and Rp by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS), as well as  BZLF1  and  BRLF1  expression by semiquantitative reverse transcription (RT)-PCR in tumors of epithelial, NK- and B-cell origins.    Results  We found that both Zp and Rp were hypermethylated in all studied EBV-positive cell lines and tumors of lymphoid (B- or NK cell) or epithelial origin, while unmethylated Zp and Rp alleles were detected in cell lines expressing  BZLF1  and  BRLF1 . Following azacytidine treatment or combined with trichostatin A (TSA), the expression of  BZLF1  and  BRLF1  was restored along with concomitant promoter demethylation, which subsequently induced the reactivation of early lytic gene  BHRF1  and late lytic gene  BLLF1 .    Conclusions  Hypermethylation of Zp and Rp mediates the frequent silencing of  BZLF1  and  BRLF1  in EBV-associated tumors, which could be reactivated by demethylation agent and ultimately initiated the EBV lytic cascade.

Methylation profiling of Epstein-Barr virus immediate-early gene promoters, BZLF1 and BRLF1in tumors of epithelial, NK- and B-cell origins