The Epstein-Barr Virus Regulome in Lymphoblastoid Cells

Publication date: 11 October 2017
Source:Cell Host & Microbe, Volume 22, Issue 4
Author(s): Sizun Jiang, Hufeng Zhou, Jun Liang, Catherine Gerdt, Chong Wang, Liangru Ke, Stefanie C.S. Schmidt, Yohei Narita, Yijie Ma, Shuangqi Wang, Tyler Colson, Benjamin Gewurz, Guoliang Li, Elliott Kieff, Bo Zhao
Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation.

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Teaser

Jiang et al. examine the 3D chromatin landscape of Epstein-Barr virus (EBV)-transformed B cells to build the EBV regulome. Viral EBNA and LMP proteins regulate host gene expression through long-range enhancer-promoter looping to activate key oncogenes and inactivate tumor suppressor genes in lymphoblastoid cells.


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