Epstein-Barr Virus (EBV) is a herpesvirus responsible for approximately 1% of cancers worldwide, including African Burkitt lymphoma, Hodgkin lymphoma, lymphomas in immunosuppressed patients, and nasopharyngeal and gastric carcinoma. Interestingly, the development of different cancers is mainly due to expression of the latent EBV proteins, although expression of lytic genes has recently been shown to play a role. Many of the molecular mechanisms behind EBV reactivation have been revealed, however, the contribution of chromatin dynamics to EBV reactivation is not well understood. A better understanding of how the switch between the latent and lytic cycle is regulated could have implications in treating disease. Here we investigate the contribution of chromatin dynamics to EBV reactivation in the context of i) nuclear localization and contacts with the human genome, and ii) the chromatin-reading protein BRD4. We used in situ Hi-C to show that the Epstein-Barr virus associates with repressive compartments of the nucleus during latency, and non-repressive compartments of the nucleus during reactivation. This adds 3D re-localization as a novel component to the molecular events that occur during EBV reactivation. Furthermore, we show that the protein BRD4 plays an important role in EBV lytic reactivation. BRD4 binds to the lytic origins of replication and inhibition of BRD4 by JQ1 inhibits the lytic cycle at two different steps. In summary, this work has led to a better understanding of how the latent-lytic switch of EBV is regulated.
|Advisor:||Miranda, JJ L.|
|Commitee:||Ott, Melanie, Panning, Barbara, Pollard, Katherine S.|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 79/02(E), Dissertation Abstracts International|
|Keywords:||Brd4, Chromatin, Epstein-barr virus, Nuclear organization, Reactivation, Transcription|
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