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

Wood, C David, Veenstra, Hildegonda, Khasnis, Sarika, Gunnell, Andrea, Webb, Helen M, Shannon-Lowe, Claire, Andrews, Simon, Osborne, Cameron S and West, Michelle J (2016) MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs. eLife, 5. e18270. ISSN 2050-084X

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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.

Item Type: Article
Keywords: Cancer, Virus, Gene, Enhancer, Transcription, MYC, Bim
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Q Science > QR Microbiology > QR0355 Virology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Michelle West
Date Deposited: 07 Sep 2016 12:54
Last Modified: 07 Mar 2017 11:08
URI: http://sro.sussex.ac.uk/id/eprint/63179

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Project NameSussex Project NumberFunderFunder Ref
How does Epstein-Barr virus contribute to the development of Burkitt's and other B-cell lymphomas?G0902LEUKAEMIA AND LYMPHOMA RESEARCH12035
Gene deregulation in lymphoma: uncovering mechanisms and pathways exploited by Epstein-Barr virusG1700LEUKAEMIA AND LYMPHOMA RESEARCH15024