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Cell Host Microbe. 2015 Feb 11;17(2):205-16. doi: 10.1016/j.chom.2014.12.013. Epub 2015 Jan 29.

Epstein-Barr virus oncoprotein super-enhancers control B cell growth.

Author information

1
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Department of Medicine and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
4
Center for Biomedical Informatics, Harvard Medical School and Division of Hematology, Children's Hospital, Boston, MA 02115, USA.
5
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ekieff@rics.bwh.harvard.edu.
6
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bzhao@partners.org.

Abstract

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.

PMID:
25639793
PMCID:
PMC4539236
DOI:
10.1016/j.chom.2014.12.013
[Indexed for MEDLINE]
Free PMC Article

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