Cell Host & Microbe
Volume 17, Issue 2, 11 February 2015, Pages 205-216
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Article
Epstein-Barr Virus Oncoprotein Super-enhancers Control B Cell Growth

https://doi.org/10.1016/j.chom.2014.12.013Get rights and content
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Highlights

  • EBV transcription factors and NF-κB subunits converge into EBV super-enhancers

  • MYC and BCL2 expression is driven by EBV super-enhancers

  • EBV super-enhancers are co-occupied by B cell transcription factors and cofactors

  • EBV super-enhancers are sensitive to perturbations

Summary

Super-enhancers are clusters of gene-regulatory sites bound by multiple transcription factors that govern cell transcription, development, phenotype, and oncogenesis. By examining Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs), we identified four EBV oncoproteins and five EBV-activated NF-κB subunits co-occupying ∼1,800 enhancer sites. Of these, 187 had markedly higher and broader histone H3K27ac signals, characteristic of super-enhancers, and were designated “EBV super-enhancers.” EBV super-enhancer-associated genes included the MYC and BCL2 oncogenes, which enable LCL proliferation and survival. EBV super-enhancers were enriched for B cell transcription factor motifs and had high co-occupancy of STAT5 and NFAT transcription factors (TFs). EBV super-enhancer-associated genes were more highly expressed than other LCL genes. Disrupting EBV super-enhancers by the bromodomain inhibitor JQ1 or conditionally inactivating an EBV oncoprotein or NF-κB decreased MYC or BCL2 expression and arrested LCL growth. These findings provide insight into mechanisms of EBV-induced lymphoproliferation and identify potential therapeutic interventions.

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