Histone deacetylase 3. Part 4
We demonstrated that HDAC3 but not HDAC2 interacts with the HCMV MIE locus. The reason that HDAC2 was not detected in our assay could be due to the fact that HDAC2 is known to interact with IE2, and this binding suppresses the repressive effect of HDAC2. At 24 hrs postinfection, the genomic region around the MIE may need to stay repressed, which could be accomplished by the action of HDAC3. This binding of HDAC3 to not only the MIE locus but also the genes upstream of MIE is intriguing. The region between the MIE and UL127 has been named as a unique region without any known function. This region is known to have binding sites for various cellular repressor proteins that help to repress the transcription of UL127. It is known that the promoter of UL127 gene is silenced during productive infection in fibroblasts. The UL126 gene has been reported as a latency-associated gene [29]. UL124 is a putative membrane glycoprotein that may be expressed late in the infection process. It will be interesting to see how the HDACs bind with those genomic regions at later times of infection.
HDAC3 has been shown to be a repressor of the viral MIE promoter. A significant increase in viral replication in the presence of the HDAC inhibitor demonstrates that the binding of HDAC3 causes inhibition of viral replication. This inhibition seems to be more pronounced at a low MOI. Host cells contain several proteins including gene expression suppressors that form a defensive arm against viral infection. HCMV has evolved strategies against cellular defense. We speculate that HCMV infection must reduce HDAC activity. Both IE1 and IE2 of HCMV were reported to functionally interact with HDACs, and IE1 of MCMV is particularly adept at reducing HDAC activity. These observations and our finding of an increase in viral replication in the presence of TSA further confirm the IE2-mediated repression of the MIE promoter by the recruitment of chromatin remodeling factors.