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Epigenetics has revealed that the Epstein-Barr virus can cause gastric cancer by altering gene expression without causing mutations to the underlying sequence.

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How EBV guts us in new ways

11 Feb 2021

The Epstein-Barr virus can cause epigenetic changes that persist even after the infection has been cleared, highlighting why prevention is better than cure when it comes to gastric cancer.

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).

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References

Okabe, A., Huang, K.K., Matsusaka, K., Fukuyo, M., Xing, M., et al. Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma. Nature Genetics. (2020) | article

About the Researcher

Patrick Tan

Executive Director

Genome Institute of Singapore
Patrick Tan is the Executive Director of the Genome Institute of Singapore and Professor at the Duke‐NUS Medical School. He directs PRISM, the SingHealth Duke‐NUS Institute of Precision Medicine, and was formerly Deputy Executive Director at A*STAR’s Biomedical Research Council. Tan has won numerous accolades for his research, including the Young Scientist Award (A‐STAR), Singapore Youth Award, SingHealth Investigator Excellence Award, Chen New Investigator Award (Human Genome Organization), President’s Science Award, and the Japanese Cancer Association International Award. In 2018, he received the American Association for Cancer Research (AACR) Team Science Award as Team Leader, representing the first time a team from Asia has received the award. He is an elected member of the American Society for Clinical Investigation (ASCI), the Bioethics Advisory Committee (BAC), a Board Member of the International Gastric Cancer Association, and co‐chair of the Singapore National Precision Medicine Program Steering Committee.

This article was made for A*STAR Research by Wildtype Media Group