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PMID: 27490482 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs.

eLife ·Vol. 5 ·2016-00-04

Wood CD, Veenstra H, Khasnis S, Gunnell A, Webb HM, Shannon-Lowe C, Andrews S, Osborne CS, West MJ

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.

Keywords
BCL2L11 EBNA2 EBNA3C Epstein-Barr virus MYC cancer biology chromosomes enhancer genes human
MeSH Terms
Bcl-2-Like Protein 11/genetics,metabolism DNA Helicases/metabolism Epstein-Barr Virus Nuclear Antigens/metabolism Gene Silencing Herpesvirus 4, Human/enzymology,physiology Nuclear Proteins/metabolism Promoter Regions, Genetic Protein Binding Proto-Oncogene Proteins c-myc/genetics,metabolism Repressor Proteins/metabolism Trans-Activators/metabolism Transcription Factors/metabolism Transcriptional Activation
Chemicals
Bcl-2-Like Protein 11 Epstein-Barr Virus Nuclear Antigens Nuclear Proteins Proto-Oncogene Proteins c-myc Repressor Proteins Trans-Activators Transcription Factors SMARCA4 protein, human DNA Helicases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wood C David
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Veenstra Hildegonda
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Khasnis Sarika
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Gunnell Andrea
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Webb Helen M
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Shannon-Lowe Claire
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Andrews Simon
Bioinformatics Group, Babraham Institute, Cambridge, United Kingdom.
Osborne Cameron S
Department of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
West Michelle J ORCID
School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Conflict of Interest

The authors declare that no competing interests exist.

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Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.18270
Published
2016-00-04
Epub
2016-00-04
Language
English
Region
England
NLM ID
101579614
PMCID
PMC5005034
Subset
IM
Grants
Medical Research Council · MR/J002046/1 · United Kingdom
Medical Research Council · MR/K01952X/1 · United Kingdom
Medical Research Council · MR/N023781/1 · United Kingdom
External Links
PubMed source DOI: 10.7554/eLife.18270 PMC Full Text View journal details
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