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Title: The control of human cytomegalovirus latent and lytic gene expression by chromatin remodelling
Author: Groves, I. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The role of chromatin structure on viral gene expression during HCMV infection of a permissive cell type was investigated. Experiments demonstrated that the MIEP was associated with chromatin throughout infection and was subject to modification consistent with the known temporal transcription of IE genes. However, immediately upon infection, the MIEP was associated with a repressed chromatin structure. This repression was relieved through use of the histone deacetylase (HDAC) inhibitor Trichostatin-A (TSA), confirming that the regulation of IE gene expression at this time was mediated by an inhibitory chromatin structure. Furthermore, down-regulation of the ND10-associated transcriptional repressor, hDaxx, which is known to interact with HDACs, led to similar relief from repression. Further analysis of promoters of prototypic viral early and late genes, UL44 and pp28 respectively, also revealed that all classes of viral genes are subject to chromatin-mediated regulation throughout productive infection. Although differentiation-dependent regulation of MIEP activity underpins viral latency and reactivation, down-regulation of the intrinsic anti-viral repressor hDaxx in in vitro latent model systems did not permit reactivation of IE gene expression. Consequently, repression of IE gene expression by hDaxx does not appear to be involved in regulation of viral latency and reactivation. In conclusion, immediately upon infection of permissive cells, intrinsic repression of HCMV IE gene transcription occurs through the establishment of an inhibitory chromatin structure around the MIEP, mediated by hDaxx and HDACs. This repression is overcome by viral factors before full productive infection can begin. Full lytic infection then involves regulation of viral gene expression through remodelling of chromatin structure at all classes of HCMV promoters.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available