Regulation of herpes simplex virus type 1 thymidine kinase gene expression by thyroid hormone receptor in cultured neuronal cells
Herpes simplex virus type 1 (HSV-1) undergoes acute infection in epithelial cells followed by establishment of latency in the neurons of trigeminal ganglia. The latent virus maintains a dormant state and can recurs spontaneously, suggesting transcriptional silencing and reactivation occur in neurons. Computer data mining identified a nuclear hormone response element (NRE), the binding site for the thyroid hormone receptor (TR) or other nuclear hormone receptor, in the promoter of HSV-1 thymidine kinase (TK). TRs are transcription factors whose activity is dependent on their ligand thyroid hormone (T3; triiodothyronine). We hypothesize that TR and T3 exert regulation on HSV-1 gene expression in neurons. A neuroblastoma cell line expressing the TR isoform β (N2aTRβ) was utilized for in vitro investigation. Results showed that liganded TR repressed TK promoter activity but unliganded TR relieved the inhibition. The mutagenesis study demonstrated that one nucleotide mutation at the NRE abolished the T3/TR-mediated regulation. N2aTRβ cells treated with T3 were suppressive to TK expression and virus release but the removal of T3 de-repressed TK expression and increased virus release, confirmed by reverse transcriptase—polymerase chain reaction (RT-PCR) and plaque assays, respectively. Chromatin immunoprecipitation (ChIP) assays showed that TRs were enriched at TK NRE in the presence of T3. Additional results demonstrated that hyper acetylated histone H4 and monomethylated H3 modified at lysine 9 (H3K9me1) were enriched at transcriptionally active TK promoters but were dissociated from the NRE by T3/TR. These results suggest that T3 could regulate HSV-1 gene expression through its receptor via histone modification in cultured neuronal cells.
Keywordsgene regulation herpes simplex virus type-1 histone acetylation histone methylation neuronal cell thymidine kinase thyroid hormone receptor
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