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

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posted on 2023-06-09, 02:46 authored by David WoodDavid Wood, Hildegonda Veenstra, Sarika Khasnis, Andrea Gunnell, Helen WebbHelen Webb, Claire Shannon-Lowe, Simon Andrews, Cameron S Osborne, Michelle WestMichelle West
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.

Funding

How does Epstein-Barr virus contribute to the development of Burkitt's and other B-cell lymphomas?; G0902; LEUKAEMIA AND LYMPHOMA RESEARCH; 12035

Gene deregulation in lymphoma: uncovering mechanisms and pathways exploited by Epstein-Barr virus; G1700; LEUKAEMIA AND LYMPHOMA RESEARCH; 15024

History

Publication status

  • Published

File Version

  • Published version

Journal

eLife

ISSN

2050-084X

Publisher

eLife Sciences Publications Ltd.

Volume

5

Page range

1-23

Article number

e18270

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-09-07

First Open Access (FOA) Date

2016-09-07

First Compliant Deposit (FCD) Date

2016-09-07

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