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.
Highlights
Epstein-Barr virus (EBV) is associated with the development of numerous lymphomas including Burkitt’s (BL), post-transplant, Hodgkin and certain NK and T-cell lymphomas
To study the mechanism of MYC activation by the EBV transcription factors (TF) EBNA2, we examined EBNA2 binding at the MYC locus using ChIP-sequencing data we obtained previously from two EBV-infected cell lines (Gunnell et al, 2016; McClellan et al, 2013)
We found that siRNA-mediated BRG1 knockdown in GM12878 cells led to a loss of MYC promoter interactions with the À556, À428 and À186/168 enhancers (Figure 4C and D). 3C did not detect any interactions between the +1.8 Mb region and the MYC promoter in the presence or absence of BRG1, consistent with its low-level interaction frequency in EBVinfected cells (Figures 1 and 3)
Summary
Epstein-Barr virus (EBV) is associated with the development of numerous lymphomas including Burkitt’s (BL), post-transplant, Hodgkin and certain NK and T-cell lymphomas. EBV was discovered in BL biopsies from sub-Saharan Africa (Epstein et al, 1964), where BL is endemic (eBL) and almost always EBV associated. BL occurs world-wide as sporadic BL (sBL) and immunodeficiency-associated BL, where EBV positivity is approximately 20% and 60%, respectively (Mbulaiteye et al, 2014). Irrespective of origin or EBV status, the defining feature of BL is a chromosomal translocation involving MYC on chromosome 8 and an immunoglobulin (IG) gene. MYC translocations detected in BL involve either the IG heavy, or lambda or kappa light chain loci on chromosomes 14, 2 or 22 respectively. The position of the MYC/IG translocation breakpoint is usually far 5’ of MYC in endemic (EBV positive) BL.
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