The latent infection of Epstein-Barr Virus (EBV) is associated with human lymphoid and epithelial cell malignancies. The viral encoded oncogenes LMP1 and EBNA2 family are expressed in some forms of latency, referred to as type III, but not in more restricted forms of latency, referred to as type I. The transition between these two latent gene expression programs balances cellular proliferation associated with type III latency and evasion of immune detection attributed to type I latency. The cellular signals and mechanisms regulating the switch between latency III and I transcription programs have not been fully elucidated. Our preliminary data indicates that EBV latency programs may be coordinated by approximately 12 kb of viral sequence spanning the divergent promoters of LMP1 and EBNA2, and encompasses the EBV latent replication origin OriP and RNA polymerase III transcribed EBER genes. We refer to this region as the EBV latency control region (LCR). We have used the chromatin immunoprecipitation (ChIP) assay to examine the chromatin architecture of the LCR in different types of EBV latency programs. We found that changes in the pattern of histone H3 K4 methylation (H3mK4) correlate with changes in latency type. We also found that the cellular chromatin boundary factor CTCF bound the LCR and limited the expansion of H3 K4 methylation in type I latency, but not in type III. We propose to further characterize the post-translational modifications and epigenetic marks that regulate the switch between latency types. We will also determine if CTCF inhibits EBNA2 transcription in type I latency, and what regulates CTCF binding to the LCR. Finally, we will investigate the signaling pathways that modulate CTCF and EBNA2 activity at the EBNA2 promoter. These studies will help to elucidate the mechanisms underlying the transitions from type I and type III EBV gene expression programs, and provide a mechanistic basis for the increased oncogenic risk of EBV-infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017336-03
Application #
7233169
Study Section
Special Emphasis Panel (ZDE1-YL (13))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2005-07-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$258,235
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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