The Epstein-Barr virus (EBV) predominantly establishes latent infection in B 
cells, and the reactivation of the virus from latency is dependent on the 
expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits 
only low basal activity but is activated in response to chemical or biological 
inducers, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), calcium 
ionophores, or histone deacetylase (HDAC) inhibitors. In some cell lines 
latently infected with EBV, an HDAC inhibitor alone can induce BZLF1 
transcription, while the treatment does not enhance expression in other cell 
lines, such as B95-8 or Raji cells, suggesting unknown suppressive mechanisms 
besides histone deacetylation in those cells. Here, we found the epigenetic 
modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 
trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Levels of active markers 
such as histone acetylation and H3K4me3 were low in latent cells but increased 
upon reactivation. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of 
H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji 
cells when in combination with an HDAC inhibitor, trichostatin A (TSA). The 
knockdown of Ezh2 or Suv420h1, histone methyltransferases for H3K27me3 or 
H4K20me3, respectively, further proved the suppression of Zp by the 
methylations. Taken together, the results indicate that H3K27 methylation and 
H4K20 methylation are involved, at least partly, in the maintenance of latency, 
and histone acetylation and H3K4 methylation correlate with the reactivation of 
the virus in Raji cells.