If the genome is analogous to a script of a play, then the epigenome is a collection of the director's notes—dramatically altering the play without rewriting the script itself. In a study published in Nature Genetics, researchers at A*STAR’s Genome Institute of Singapore (GIS) have found that the Epstein-Barr virus (EBV) is like a director gone rogue, altering the host epigenome to transform healthy cells into cancerous ones.
“While EBV infection is known to be associated with 8-10 percent of gastric cancers, the exact manner by which EBV causes gastric cancer remains poorly understood,” said Patrick Tan, Executive Director of GIS and Professor at Duke‐NUS Medical School. While other cancer-causing viruses are known to cause disease by integrating into the genome and disrupting the host DNA, Tan and his team have shown the EBV can affect gene regulation without integrating its DNA.
Instead of looking for cancer-induced changes at the level of individual genes, the researchers investigated epigenetic alterations and changes in the 3D structure of DNA. “Using a technique called Hi-C, we identified paired regions of the genome that lie in close physical proximity to one another in 3D space, that would otherwise exist far apart if the DNA sequence is interpreted as a linear sequence of base pairs,” Tan said.
By comparing these 3D chromatin structures between healthy and cancerous stomach cell lines, the researchers identified a novel mechanism for tumor formation, which they termed “enhancer infestation”. In the enhancer infestation model, the virus unleashes normally silenced enhancers, which are short pieces of DNA that augment gene expression, allowing them to activate nearby tumor-enhancing genes by loosening their tightly packed chromatin structure. “This is a new paradigm where viral DNA, even when not integrated, can nevertheless interact with the human genome to affect gene regulation, particularly in genes related to the development of cancer.”
Further work showed that EBV modified chromatin topologies by altering the epigenetic ‘tags’ on histone H3, a DNA packaging protein. Interestingly, the group found that these tags persisted even after EBV DNA was eliminated. “These results suggest that for such genes, the ‘epigenetic damage’ caused by EBV is largely fixed and that infected cells are committed to the development of cancer,” Tan added.
The group, led by Tan and Atsushi Kaneda of Chiba University, Japan, is now investigating if the enhancer infestation model applies to other EBV-related cancer types. Moreover, having identified several novel genes linked to gastric cancer using this approach, the researchers are now investigating whether these genes are suitable drug targets.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).
