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PMID: 25540416 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Epstein-Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 112 ·No. 2 ·2015-01-13 ·Pages 554-9

Schmidt SC, Jiang S, Zhou H, Willox B, Holthaus AM, Kharchenko PV, Johannsen EC, Kieff E, Zhao B

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.

Keywords
BATF CDKN2A EBNA3A IRF4 RUNX3
MeSH Terms
B-Lymphocytes/metabolism,virology Basic-Leucine Zipper Transcription Factors/metabolism Binding Sites/genetics Cell Line Chemokine CXCL10/genetics Chemokine CXCL9/genetics Core Binding Factor Alpha 3 Subunit/metabolism Cyclin D2/genetics DNA/genetics,metabolism Enhancer Elements, Genetic Epstein-Barr Virus Nuclear Antigens/genetics,metabolism Genes, bcl-2 Genes, myc Genes, p16 Genome, Human Genome, Viral Herpesvirus 4, Human/genetics,pathogenicity,physiology Host-Pathogen Interactions/genetics Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism Interferon Regulatory Factors/metabolism Promoter Regions, Genetic Viral Proteins/genetics,metabolism
Chemicals
BATF protein, human Basic-Leucine Zipper Transcription Factors CCND2 protein, human CXCL10 protein, human CXCL9 protein, human Chemokine CXCL10 Chemokine CXCL9 Core Binding Factor Alpha 3 Subunit Cyclin D2 EBNA-2 protein, Human herpesvirus 4 EBNA-3A antigen EBNA-3C, epstein-barr virus EBNA-LP protein, Human herpesvirus 4 Epstein-Barr Virus Nuclear Antigens Immunoglobulin J Recombination Signal Sequence-Binding Protein Interferon Regulatory Factors RBPJ protein, human Runx3 protein, human Viral Proteins interferon regulatory factor-4 DNA
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Schmidt Stefanie C S
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
Jiang Sizun
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
Zhou Hufeng
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
Willox Bradford
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
Holthaus Amy M
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
Kharchenko Peter V
Center for Biomedical Informatics, Harvard Medical School and Division of Hematology, Children's Hospital, Boston, MA 02115; and.
Johannsen Eric C
Department of Medicine and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706.
Kieff Elliott
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.
Zhao Bo
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1422580112
Email
ekieff@rics.bwh.harvard.edu
Published
2015-01-13
Epub
2014-00-24
Pages
554-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4299249
Subset
IM
Grants
NCI NIH HHS · R01CA170023 · United States
NCI NIH HHS · R01 CA047006 · United States
NCI NIH HHS · R01CA047006 · United States
NCI NIH HHS · R01CA085180 · United States
NCI NIH HHS · R01 CA170023 · United States
NCI NIH HHS · R01 CA085180 · United States
Databases
GEO
GSE59181
External Links
PubMed source DOI: 10.1073/pnas.1422580112 PMC Full Text View journal details
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