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|Title:||Activation of the endogenous alpha-globin gene in non-erythroid cells by herpes simplex virus|
|Advisor:||Smiley, Jim R.|
|Abstract:||<p>During lytic infection, herpes simplex virus (HSV) usurps the host cell machineries to facilitate viral gene expression, and executes viral-directed host shutoff activities to strongly inhibit expression of endogenous cellular genes. Our laboratory has previously observed that, in contrast to the fate of the majority of host genes, the α-globin gene in non-erythroid cells is activated upon HSV infection. This finding is intriguing not only because this cellular gene escapes the viral host shutoff functions, but also because this tissue-specific gene is normally repressed in non-erythroid cells. The series of studies presented in this thesis document the characterisation and analysis of this phenomenon. HSV immediate-early proteins ICP0 and ICP4 were each found to be capable of inducing expression of the previously silent α-globin gene in non-erythroid cells. ICP4 was the dominant viral transactivator responsible for transcriptional activation of the α-globin gene during infection, whereas ICP0 may indirectly activate expression of this gene by disrupting its tissue-specific regulation. Efficient accumulation of α-globin transcripts in HSV-infected cells also required the presence of ICP22 which appeared to regulate expression of the α-globin gene at a post-transcriptional level. In addition, ICP27 induced accumulation of unspliced α-globin premRNA. Analysis of the chromatin structure of the endogenous α-globin gene showed that an array of nucleosomes are positioned along the coding region of this gene. Furthermore, activation of the α-globin gene by HSV resulted in subtle alteration of the positioning of the nucleosome located at the TATA box and transcription start site of the gene, suggesting the positioning of this nucleosome may be involved in the repression of this gene in non-erythroid cells. Taken together, the results from this thesis project showed that at least four viral proteins are involved in the activation and expression of the α-globin gene in HSV-infected cells and this activation may be mediated by alteration of the chromatin structure of the endogenous α-globin locus.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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