How the Epstein-Barr virus takes control of two genes involved in cancer development so it can switch them on or off has been uncovered by scientists at the University of Sussex.

The research team set out to determine how the Epstein-Barr virus controls two genes; MYC, a gene known to drive cancer development when it is altered or switched on at high level and BCL2L11, a gene which normally triggers cell death to prevent cancer, but can be turned off by the virus.

The scientists found that the virus manipulates 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.

Burkitt’s Lymphoma

Professor West’s 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.

[caption id=“attachment_82156” align=“aligncenter” width=“1200”]mechanism of MYC activation Model showing the mechanism of MYC activation and BCL2L11 repression by EBV transcription factors.
(A) In uninfected B cells, MYC promoter interactions with downstream enhancers dominate. MYC activation on EBV infection by the EBV TF EBNA2 occurs through the activation of three major clusters of upstream enhancers at −556, −428 and −186/168 kb (indicated by black boxes). This is associated with increased H3K27ac and BRG1 binding. EBNA2 promotes interactions between the MYC promoter and these upstream enhancers and reduces interactions with downstream enhancers. As part of this three-dimensional MYC enhancer reorganisation, EBNA2 also increases interactions between CTCF-bound regions (asterisks) in the −556 kb super-enhancer. (B) BCL2L11 is repressed on EBV-infection by the EBV repressors EBNA3A and EBNA3C through the inactivation of multiple enhancers in regulatory hub encompassing the ACOXL gene. Enhancer inactivation is associated with PRC2 (EZH2) binding, increased H3K27me3 and the loss of enhancer-promoter interactions. Arrows indicate transcription start sites. Genes are indicated as expressed (+) or repressed (−). ACOXL is repressed or expressed at low-level (±).

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. Encouragingly the team have discovered that this blocking effect can be reversed by using a specific drug - paving the way for new treatments.

Professor Michelle West, research team leader from the University of Sussex, said:

“This is a key step towards uncovering how this common virus which, affects thousands of people every year, causes blood cancer.

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."

Complex Genetic Interactions

Dr Alasdair Rankin, Research Director at Bloodwise, said:

“We have known for many years that the Epstein-Barr virus causes various types of lymphoma, but we were never sure of the exact mechanisms. These new findings have shed light on how the virus is able to drive blood cancer development by altering the behavior of genes that control cancer growth.

By mapping out the complex genetic interactions that help lymphoma cells grow and survive, this research can guide the design of new treatments to target the disease. It may also help to identify those drugs currently used to treat other diseases that could be effective in treating these types of lymphoma."

Professor West has received a grant from the blood cancer charity Bloodwise for two research projects that are helping to uncover how a number of common types of leukaemia and lymphoma arise in children and adults and to find new ways to treat them. The research team are studying how the common Epstein-Barr virus can sometimes trigger the development of blood cancers including Burkitt and Hodgkin lymphomas.

C David Wood et al. Activation and silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs eLife (2016). DOI: 10.7554/eLife.18270

Image: Professor Michelle West. Credit: University of Sussex

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