title: Epstein-Barr virus nuclear antigen leader protein localizes to promoters and enhancers with cell transcription factors and EBNA2.
abstract: Epstein-Barr virus (EBV) nuclear antigens EBNALP (LP) and EBNA2 (E2) are coexpressed in EBV-infected B lymphocytes and are critical for lymphoblastoid cell line outgrowth. LP removes NCOR and RBPJ repressive complexes from promoters, enhancers, and matrix-associated deacetylase bodies, whereas E2 activates transcription from distal enhancers. LP ChIP-seq analyses identified 19,224 LP sites of which ~50% were ± 2 kb of a transcriptional start site. LP sites were enriched for B-cell transcription factors (TFs), YY1, SP1, PAX5, BATF, IRF4, ETS1, RAD21, PU.1, CTCF, RBPJ, ZNF143, SMC3, NFκB, TBLR, and EBF. E2 sites were also highly enriched for LP-associated cell TFs and were more highly occupied by RBPJ and EBF. LP sites were highly marked by H3K4me3, H3K27ac, H2Az, H3K9ac, RNAPII, and P300, indicative of activated transcription. LP sites were 29% colocalized with E2 (LP/E2). LP/E2 sites were more similar to LP than to E2 sites in associated cell TFs, RNAPII, P300, and histone H3K4me3, H3K9ac, H3K27ac, and H2Az occupancy, and were more highly transcribed than LP or E2 sites. Gene affected by CTCF and LP cooccupancy were more highly expressed than genes affected by CTCF alone. LP was at myc enhancers and promoters and of MYC regulated ccnd2, 23 med complex components, and MYC regulated cell survival genes, igf2r and bcl2. These data implicate LP and associated TFs and DNA looping factors CTCF, RAD21, SMC3, and YY1/INO80 chromatin-remodeling complexes in repressor depletion and gene activation necessary for lymphoblastoid cell line growth and survival.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Department of Microbiology and Immunobiology, Harvard University, Boston, MA 02115.
authors.forename: Daniel
authors.initials: D
authors.lastname: Portal
authors.forename: Hufeng
authors.initials: H
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lowry
authors.forename: Limsoon
authors.initials: L
authors.lastname: Wong
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Dustin
authors.initials: D
authors.lastname: Holloway
authors.forename: Sizun
authors.initials: S
authors.lastname: Jiang
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002144:Callithrix; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C402641:EBNA-2 protein, Human herpesvirus 4; C402640:EBNA-LP protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D014157:Transcription Factors; D014764:Viral Proteins
keywords: gene expression; genome-wide ChIP-seq analysis