title: RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.
abstract: In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (-139 to -250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gunnell
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Webb
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: C David
authors.initials: CD
authors.lastname: Wood
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McClellan
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Billy
authors.initials: B
authors.lastname: Wichaidit
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, Marchioninistraße 25, 81377 Munich, Germany German Centre for Infection Research (DZIF), Partner site Munich, Helmholtz Center Munich, German Research Center for Environmental Health, Marchioninistraße 25, 81377 Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jenner
authors.affiliation: Department of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Cameron
authors.initials: C
authors.lastname: Osborne
authors.affiliation: Department of Medicine, Virology Section, St Mary's Hospital Campus, Imperial College, London W2 1PG, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Farrell
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK m.j.west@sussex.ac.uk.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: West
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D050657:Core Binding Factor alpha Subunits / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050657:Core Binding Factor alpha Subunits; C508151:EBNA-3A antigen; C422762:EBNA-3B antigen; C438197:EBNA4 antigen; D019309:Epstein-Barr Virus Nuclear Antigens; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; C493728:RUNX1 protein, human; D051880:Receptors, Notch; C493729:Runx3 protein, human; D014157:Transcription Factors