MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs
- University of Sussex, United Kingdom
- University of Birmingham, United Kingdom
- Babraham Institute, United Kingdom
- King's College London School of Medicine, United Kingdom
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.
Data availability
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MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubsPublicly available at the NCBI Gene Expression Omnibus (accession number: GSE82150).
Article and author information
Author details
Funding
Bloodwise (12035)
- Michelle J West
Bloodwise (15024)
- Michelle J West
Bloodwise (14007)
- Cameron S Osborne
Medical Research Council (MR/J002046/1)
- Claire Shannon-Lowe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Nick J Proudfoot, University of Oxford, United Kingdom
Version history
- Received: May 28, 2016
- Accepted: August 3, 2016
- Accepted Manuscript published: August 4, 2016 (version 1)
- Version of Record published: August 30, 2016 (version 2)
Copyright
© 2016, Wood et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs
eLife 5:e18270.
https://doi.org/10.7554/eLife.18270
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