title: Epstein-Barr virus oncoprotein super-enhancers control B cell growth.
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.
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Hufeng
authors: H
authors: Zhou
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Stefanie C S
authors: SC
authors: Schmidt
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Sizun
authors: S
authors: Jiang
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Bradford
authors: B
authors: Willox
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Katharina
authors: K
authors: Bernhardt
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Jun
authors: J
authors: Liang
authors: Department of Medicine and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Eric C
authors: EC
authors: Johannsen
authors: Center for Biomedical Informatics, Harvard Medical School and Division of Hematology, Children's Hospital, Boston, MA 02115, USA.
authors: Peter
authors: P
authors: Kharchenko
authors: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Benjamin E
authors: BE
authors: Gewurz
authors: 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.
authors: Elliott
authors: E
authors: Kieff
authors: 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.
authors: Bo
authors: B
authors: Zhao
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology*; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D014764:Viral Proteins
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