Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification

• Published in: Virology journal Vol. 4; no. 1; p. 56
• Main Authors: Pinnoji, Rajeswara C, Bedadala, Gautam R, George, Beena, Holland, Thomas C, Hill, James M, Hsia, Shao-chung V
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07.06.2007; BioMed Central; BMC
• Subjects: Binding Sites - genetics; Cell Line; Gene expression; Gene Expression Regulation, Viral; Genes, Reporter; Genetic aspects; Herpes simplex virus; Herpesvirus 1, Human - genetics; Histone Deacetylase Inhibitors; Histones; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Physiological aspects; Repressor proteins; Repressor Proteins - physiology; Transcription Factors - physiology; Transcription, Genetic; Viral Regulatory and Accessory Proteins; United States
• ISSN: 1743-422X; 1743-422X
• DOI: 10.1186/1743-422X-4-56

During primary infection of its human host, Herpes Simplex Virus Type-1 (HSV-1) establishes latency in neurons where the viral genome is maintained in a circular form associated with nucleosomes in a chromatin configration. During latency, most viral genes are silenced, although the molecular mechanisms responsible for this are unclear. We hypothesized that neuronal factors repress HSV-1 gene expression during latency. A search of the HSV-1 DNA sequence for potential regulatory elements identified a Repressor Element-1/Neuronal Restrictive Silencer Element (RE-1/NRSE) located between HSV-1 genes ICP22 and ICP4. We predicted that the Repressor Element Silencing Transcription Factor/Neuronal Restrictive Silencer Factor (REST/NRSF) regulates expression of ICP22 and ICP4. Transient cotransfection indicated that REST/NRSF inhibited the activity of both promoters. In contrast, cotransfection of a mutant form of REST/NRSF encoding only the DNA-binding domain of the protein resulted in less inhibition. Stably transformed cell lines containing episomal reporter plasmids with a chromatin structure showed that REST/NRSF specifically inhibited the ICP4 promoter, but not the ICP22 promoter. REST/NRSF inhibition of the ICP4 promoter was reversed by histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). Additionally, chromatin immuno-precipitation (ChIP) assays indicated that the corepressor CoREST was recruited to the proximity of ICP4 promoter and that acetylation of histone H4 was reduced in the presence of REST/NRSF. Since the ICP4 protein is a key transactivator of HSV-1 lytic cycle genes, these results suggest that REST/NRSF may have an important role in the establishment and/or maintenance of HSV-1 gene silencing during latency by targeting ICP4 expression.