title: MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs.
abstract: Lymphomagenesis in the presence of deregulated MYC requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that the EBNA2 transactivator activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers and BRG1 is required for enhancer-promoter interactions in EBV-infected cells. At BCL2L11, we identify a haematopoietic enhancer hub that is inactivated by the EBV repressors EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2. Reversal of enhancer inactivation using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. EBV therefore drives lymphomagenesis by hijacking long-range enhancer hubs and specific cellular co-factors. EBV-driven MYC enhancer activation may contribute to the genesis and localisation of MYC-Immunoglobulin translocation breakpoints in Burkitt's lymphoma.
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: C David
authors.initials: CD
authors.lastname: Wood
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Hildegonda
authors.initials: H
authors.lastname: Veenstra
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Sarika
authors.initials: S
authors.lastname: Khasnis
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gunnell
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Webb
authors.affiliation: Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.affiliation: Bioinformatics Group, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Andrews
authors.affiliation: Department of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Osborne
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Michelle J
authors.identifier: 0000-0002-9497-9365
authors.initials: MJ
authors.lastname: West
mesh_terms: D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D020868:Gene Silencing; D004854:Herpesvirus 4, Human / Q000201:enzymology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000072224:Bcl-2-Like Protein 11; D019309:Epstein-Barr Virus Nuclear Antigens; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: BCL2L11; EBNA2; EBNA3C; Epstein-Barr virus; MYC; cancer biology; chromosomes; enhancer; genes; human