Epstein Barr Virus Drives Cancer Through Transcriptional Regulation and Chromatin Dynamics
CitationJiang, Sizun. 2017. Epstein Barr Virus Drives Cancer Through Transcriptional Regulation and Chromatin Dynamics. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractEpstein Barr Virus (EBV), the prototypical human tumor virus, transforms human B cells to establish immortalized Lymphoblastoid Cell Lines (LCLs). In LCLs, EBV expresses six viral transcription factors (EBV Nuclear Antigens) and requires the NF-kB family of cellular transcription factors for growth and survival. Recent works identify crucial roles that DNA regulatory elements, such as enhancers, play in transcriptional regulation of developmental processes, cell identify and disease. In addition, deregulation of the spatial organization of chromatin is proposed as a novel driver of cancer. I propose that EBV utilizes transcription and chromatin organization in lymphomagenesis.
In this work, I will systematically examine the nuclear functions of EBV transcription factors and its interplay with host DNA binding factors. I will first begin by describing the binding landscape of two of these proteins: EBNA3A and EBNA3C, two factors that astonishingly do not bind DNA intrinsically, but are bound to distinct regions of the human chromatin through host factors. Next, I will describe our efforts in the identification and characterization of EBV Super Enhancers: highly active enhancer clusters with crucial roles in EBV-driven proliferation. Thereafter, I will present functional evidence for EBV-mediated long-range chromatin interactions, in both activating and repressive contexts, to drive disease. Lastly, I will introduce an interesting function of the EBNA3C oncoprotein in repressing cellular enhancers and blocking long-range interactions on chromatin.
Historically, viruses have been incredible tools in elucidating molecular mechanisms in biology. Taken together, this work will shed light on how EBV drives disease through rewiring of the human nucleus, and unravel fundamental biological processes in lymphocyte chromatin organization and transcriptional regulation.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41140226
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