Epstein Barr Virus (EBV) is causally related to Burkitt's Lymphoma, Hodgkin's Lymphoma, and Lymphoproliferative Diseases in immune suppressed and HIV infected people. In humans deficient in T cell immune responses, Latency III infected B-cells can be highly malignant. EBV conversion of Resting B Lymphocytes to continuously proliferating Lymphoblasts (LCLs) by expressing Latency III EBV nuclear antigens EBNA2, LP, 3A, 3C, and Latent Membrane Protein LMP1, is a relevant and experimentally useful model for EBV oncogenesis. EBNA3A and EBNA3C are essential for LCL growth and they regulate the expression of hundreds of cell genes. EBNA3A and EBNA3C bind to thousands of enhancer sites and alter enhancer-promoter looping. EBNA3A and 3C suppress CDKN2A/B p16INK4A and p14ARF expression to enable continuous cell proliferation. To further characterize the molecular mechanisms through which EBNA3A and EBNA3C regulate transcription, our specific aims are to: 1. Determine the effect of EBNA3A/3C on genome reorganization and their effect on LCL growth using Hi-C and ChIA-PET. 2. Determine the mechanisms through which EBNA3A/3C suppress senescence by examining the effect of EBNA3A/3C on enhancer/silencer promoter looping at the CDKN2A/B loci. 3. Determine the molecular mechanisms by which EBNA3A/C are tethered to DNA. These studies will provide new insights on how EBNA3A and EBNA3C contribute to EBV mediated growth transformation.
Epstein Barr Virus (EBV) associated malignancies are a significant threat to humans. These studies will elucidate the molecular basis through which EBV proteins EBNA3A and EBNA3C exploit the normal B lymphocyte transcription program to achieve immortal growth and identify potential targets for intervention.
|Wang, Chong; Zhou, Hufeng; Xue, Yong et al. (2018) Epstein-Barr Virus Nuclear Antigen Leader Protein Coactivates EP300. J Virol 92:|
|Jiang, Sizun; Zhou, Hufeng; Liang, Jun et al. (2017) The Epstein-Barr Virus Regulome in Lymphoblastoid Cells. Cell Host Microbe 22:561-573.e4|
|Ke, Liangru; Zhou, Hufeng; Wang, Chong et al. (2017) Nasopharyngeal carcinoma super-enhancer-driven ETV6 correlates with prognosis. Proc Natl Acad Sci U S A 114:9683-9688|
|Wang, Anqi; Welch, Rene; Zhao, Bo et al. (2016) Epstein-Barr Virus Nuclear Antigen 3 (EBNA3) Proteins Regulate EBNA2 Binding to Distinct RBPJ Genomic Sites. J Virol 90:2906-19|
|Liang, Jun; Zhou, Hufeng; Gerdt, Catherine et al. (2016) Epstein-Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation. Proc Natl Acad Sci U S A 113:14121-14126|
|Shen, Chih-Lung; Liu, Cheng-Der; You, Ren-In et al. (2016) Ribosome Protein L4 is essential for Epstein-Barr Virus Nuclear Antigen 1 function. Proc Natl Acad Sci U S A 113:2229-34|
|Ohashi, Makoto; Holthaus, Amy M; Calderwood, Michael A et al. (2015) The EBNA3 family of Epstein-Barr virus nuclear proteins associates with the USP46/USP12 deubiquitination complexes to regulate lymphoblastoid cell line growth. PLoS Pathog 11:e1004822|
|Schmidt, Stefanie C S; Jiang, Sizun; Zhou, Hufeng et al. (2015) Epstein-Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes. Proc Natl Acad Sci U S A 112:554-9|
|Zhou, Hufeng; Schmidt, Stefanie C S; Jiang, Sizun et al. (2015) Epstein-Barr virus oncoprotein super-enhancers control B cell growth. Cell Host Microbe 17:205-16|
|Jiang, Sizun; Willox, Bradford; Zhou, Hufeng et al. (2014) Epstein-Barr virus nuclear antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. Proc Natl Acad Sci U S A 111:421-6|
Showing the most recent 10 out of 35 publications