title: Epstein-Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes.
abstract: Epstein-Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up-regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16(INK4A) and p14(ARF)-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16(INK4A) and p14(ARF), enabling continuous cell proliferation. Analyses of the EBNA3A human genome-wide ChIP-seq landscape revealed 37% of 10,000 EBNA3A sites to be at strong enhancers; 28% to be at weak enhancers; 4.4% to be at active promoters; and 6.9% to be at weak and poised promoters. EBNA3A colocalized with BATF-IRF4, ETS-IRF4, RUNX3, and other B-cell Transcription Factors (TFs). EBNA3A sites clustered into seven unique groups, with differing B-cell TFs and epigenetic marks. EBNA3A coincidence with BATF-IRF4 or RUNX3 was associated with stronger EBNA3A ChIP-Seq signals. EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1. ChIP-re-ChIP revealed complexes of EBNA3A on DNA with BATF. These data strongly support a model in which EBNA3A is tethered to DNA through a BATF-containing protein complexes to enable continuous cell proliferation.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Stefanie C S
authors.initials: SC
authors.lastname: Schmidt
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Sizun
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Hufeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Bradford
authors.initials: B
authors.lastname: Willox
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Amy M
authors.initials: AM
authors.lastname: Holthaus
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School and Division of Hematology, Children's Hospital, Boston, MA 02115; and.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: Department of Medicine and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Johannsen
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115; ekieff@rics.bwh.harvard.edu.
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics; D054370:Chemokine CXCL9 / Q000235:genetics; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D056742:Cyclin D2 / Q000235:genetics; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics* / Q000378:metabolism; D019254:Genes, bcl-2; D016259:Genes, myc; D019942:Genes, p16; D015894:Genome, Human; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D050677:Core Binding Factor Alpha 3 Subunit; D056742:Cyclin D2; D004247:DNA; D019309:Epstein-Barr Virus Nuclear Antigens; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D050835:Interferon Regulatory Factors; D014764:Viral Proteins; D000099218:Interferon Regulatory Factor-4; C099359:BATF protein, human; C080336:CCND2 protein, human; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; C402641:EBNA-2 protein, Human herpesvirus 4; C508151:EBNA-3A antigen; C498774:EBNA-3C, epstein-barr virus; C402640:EBNA-LP protein, Human herpesvirus 4; C497570:RBPJ protein, human; C493729:Runx3 protein, human
keywords: BATF; CDKN2A; EBNA3A; IRF4; RUNX3