Image by Ed Uthman
Results of research published in eLIFE appear to explain how Epstein-Barr virus (EBV) controls a pair of genes to drive lymphomagenesis.
Researchers set out to determine how EBV controls MYC, which is known to drive lymphoma development when activated, and BCL2L11, a gene that normally triggers apoptosis to prevent lymphoma but can be silenced by EBV.
The team discovered that EBV controls MYC and BCL2L11 by hijacking enhancer regions of DNA, 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 researchers found that EBV activates MYC by increasing contacts between a specific set of enhancers and the gene.
The team said an Epstein-Barr nuclear antigen, EBNA2, activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream enhancer-promoter interactions and decrease downstream interactions.
They noted that 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 researchers also discovered new enhancers that control BCL2L11. In this case, though, EBV stops these control centers from contacting the gene.
Specifically, the team found a hematopoietic enhancer hub that is inactivated by the Epstein-Barr nuclear antigens EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2.
Therefore, the researchers set out to determine if an EZH1/2 inhibitor, UNC1999, could reverse this effect. They found that UNC1999 did reverse enhancer inactivation, upregulated BCL2L11, and induced apoptosis in EBV-positive Burkitt lymphoma cells.
“This is a key step towards uncovering how this common virus, which affects thousands of people every year, causes blood cancer,” said study author Michelle West, PhD, of the University of Sussex in Brighton, UK.
“It is now important to carry out further studies to determine how the Epstein-Barr virus controls other genes that are associated with lymphoma. This will tell us more about how the virus drives lymphoma development and will help to identify new ways of targeting Epstein-Barr virus-infected cancer cells with specific drugs.”
