The scientists discovered that the virus controls the MYC and BCL2L11 genes by hijacking 'enhancer' DNA regions which are situated far away from the genes. These enhancers act as 'control centers’ and are able to contact and control genes from long distances by the looping out of the intervening stretches of DNA.
The team found that Epstein-Barr virus turns on the MYC gene by increasing contacts between a specific set of enhancers and the gene. The scientists believe this may explain how the virus causes the changes to the MYC gene that are found in Burkitt's lymphoma.
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.
The team also discovered new enhancers which control the BCL2L11 gene. In this case, they found that Epstein-Barr virus stops these control centers from contacting the gene. At BCL2L11, they identify a haematopoietic enhancer hub that is inactivated by the EBV repressors EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2.
Encouragingly the team have discovered that this blocking effect can be reversed by using a specific drug - paving the way for new treatments. 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 cofactors.
EBV-driven MYC enhancer activation may contribute to the genesis and localisation of MYC-Immunoglobulin translocation breakpoints in Burkitt’s lymphoma.