Abstract
Gammaherpesviruses have a common biological characteristic, latency and lytic replication. The balance between these two phases in murine gammaherpesvirus 68 (MHV-68) is controlled by the replication and transcription activator (RTA) gene. In this report, we investigated the effect of DNA demethylation and histone acetylation on MHV-68 replication. We showed that distinctive methylation patterns were associated with MHV-68 at the RTA promoter during latency or lytic replication. Treatment of MHV-68 latently-infected S11E cells with a DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AzaC), only weakly reactivated MHV-68, despite resulted in demethylation of the viral RTA promoter. In contrast, treatment with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) strongly reactivated MHV-68 from latency, and this was associated with significant change in histone H3 and H4 acetylation levels at the RTA promoter. We further showed that HDAC3 was recruited to the RTA promoter and inhibited RTA transcription during viral latency. However, TSA treatment caused rapid removal of HDAC3 and also induced passive demethylation at the RTA promoter. In vivo, we found that the RTA promoter was hypomethylated during lytic infection in the lung and that methylation level increased with virus latent infection in the spleen. Collectively, our data showed that histone acetylation, but not DNA demethylation, is sufficient for effective reactivation of MHV-68 from latency in S11E cells.
Highlights
Murine gammaherpesvirus 68 (MHV-68, referred to as cHV68), is a member of the gammaherpesvirus subfamily [1]
We show that histone acetylation is sufficient for MHV68 reactivation from latency in S11E cells, and this process is accompanied by demethylation of the replication and transcription activator (RTA) promoter
trichostatin A (TSA) treatment led to removal of HDAC3 complex from latent RTA promoter and viral reactivation (Fig. 4)
Summary
Murine gammaherpesvirus 68 (MHV-68, referred to as cHV68), is a member of the gammaherpesvirus subfamily [1]. MHV-68 is phylogenetically related to two other human gammaherpesviruses, Epstein-Barr Virus (EBV) and Kaposi’s sarcomaassociated herpesvirus (KSHV), which are associated with lymphoproliferative diseases and several human tumors [1,2,3,4]. Latent infection is thought to be important for tumorigenesis associated with these viruses. Reactivation from latency to lytic replication is essential for transmission of the virus from host to host; it has been suggested that even low-frequency viral reactivation plays a significant role in viral pathogenesis [6,8]. RTA is regarded as a ‘‘molecular switch’’ controlling reactivation of KSHV and MHV-68; both KSHV RTA and MHV-68 RTA are sufficient and necessary to reactivate their respective viruses from latently infected cells [10,13,14,15]
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