Histone deacetylase 3
Evidence suggests that genome chromatinization and the posttranslational modification of histones are involved in the regulation of viral gene expression, including the human cytomegalovirus (HCMV). We performed a ChIP-on-Chip assay to determine whether histone deacetylases (HDACs) interact with HCMV genomic DNA on a global level. Surprisingly, we found that HDAC3, but not HDAC2, interacts not only with the major immediate early (MIE) promoter but also with the entire MIE locus, suggesting a heterogeneous interaction of HDAC3 with HCMV DNA. The interaction of HDAC3 with the MIE region is related to inhibition of viral replication because HDAC3 inhibitors enhanced HCMV replication.
Human cytomegalovirus (HCMV) is a ubiquitous virus and infects a majority of the general population (50-90%). The fact that the incidence of cytomegalic inclusion disease (CID) is intimately related to viral burden suggests that the inhibition of viral production by the specific repression of viral gene expression will reduce the occurrence of CID. Understanding the mechanism of HCMV gene regulation is the pre-requisite for developing drugs that interfere with viral replication by repressing viral gene expression. The HCMV major immediate early (MIE) gene products, IE1 and IE2, are among the first de novo-expressed viral proteins that are required for subsequent viral gene expression and hence viral replication. IE1 and IE2 mRNAs are encoded by the major IE locus that spans from 169 to175 kbp of the viral genome and are produced by alternative splicing and differential polyadenylation. IE1 and IE2 share the first 85 amino acids. MIE genes are controlled by a strong promoter/enhancer that contains many regulatory elements.
Different cellular mechanisms have been found to play roles in inhibiting viral gene expression, and one of the most prominent ones is gene silencing through viral DNA chromatinization (also called chromatin remodeling), a procedure carried out by histone or histone-related proteins, such as histone acetylase (HAT) and histone deacetylase (HDAC). Several posttranslational modifications of histone proteins have been defined to be involved in chromatin remodeling, including acetylation by HAT, deacetylation by HDAC, SUMOylation by SUMO (Small Ubiquitin-like Modifier)-related pathway, deSUMOylation by SENP (a SUMO-specific protease) family enzymes, phosphorylation by kinase pathways, and methylation via methylases. Those enzymatic pathways orchestrate to regulate cellular gene transcription and are termed as epigenetic codes. Viral gene transcription requires cellular machinery, which is probably also regulated by cellular gene regulatory pathways. Histones are abundant nuclear proteins and have been shown to bind with HCMV genomic DNA. Therefore, it was reasonable to propose that chromatin remodeling of viral DNA takes place in the nucleus, which speculation was validated when the fact that HDAC inhibitors can promote cytomegalovirus production was also confirmed.