Epigenetic modification of the Epstein-Barr virus BZLF1 promoter regulates viral reactivation from latency

The Epstein–Barr virus (EBV) is an oncogenic human gamma-herpesvirus that predominantly establishes latent infection in B lymphocytes. Viral genomes exist as extrachromosomal episomes with a nucleosomal structure. Maintenance of virus latency or execution of reactivation is controlled by the expression of BZLF1, a viral immediate-early gene product, tightly controlled at the transcriptional level. In this article, we review how BZLF1 transcription is controlled, in other words how virus reactivation is regulated, especially in terms of epigenetics. We recently found that histone H3 lysine 27 trimethylation (H3K27me3) and H4K20me3 markers are crucial for suppression of BZLF1 in latent Raji cells. In addition, H3K9me2/3, heterochromatin protein 1, and H2A ubiquitination are associated with latency, whereas positive markers, such as higher histone acetylation and H3K4me3, are concomitant with reactivation. Since lytic replication eventually causes cell cycle arrest and cell death, development of oncolytic therapy for EBV-positive cancers is conceivable using epigenetic disruptors. In addition, we note the difficulties in analyzing roles of epigenetics in EBV, including issues like cell type dependence and virus copy numbers.