The Epstein-Barr virus (EBV) is one of the most common human viruses found all over the world. It spreads via bodily fluids, especially saliva, and causes what many may be familiar with – infectious mononucleosis, or mono. This virus, when in its latent form in humans, can also lead to cancer of the upper-throat, or nasopharyngeal carcinoma (NPC). Researchers from University of Wisconsin-Madison have discovered that an epigenetic mechanism known as DNA hydroxymethylation can alter the virus’s DNA and impact the proliferation of NPC.
EBV is either lytic or latent when it infects human cells. When the virus makes infectious particles in attempt to branch out to other cells, it’s considered to be in its lytic form. EBV is in its latent form when the immune system is able to combat the lytic form of the virus and force it to hide in its host cells. Even though EBV is not actively replicating when it’s latent, sections of the virus’s genome are still being expressed and creating oncogenic proteins that help form cancer. It’s actually when EBV is in its latent stage that the cancer begins to form in the nasopharynx, or the uppermost area of the throat located right behind the nasal cavity that it’s connected to.
In a study published in PNAS, scientists found that DNA hydroxymethylation, an epigenetic mechanism that affects the DNA without changing the underlying sequence, reverts the virus from its latent form to its lytic form. This lytic reactivation allows the virus to infect numerous other cells within the nasopharynx and spread the cancer-causing virus.
DNA hydroxymethylation remains a mysterious epigenetic mechanism that’s still not completely understood by scientists. The function of 5-hydroxymethylcytosine (5-hmC), termed the “sixth base”, is still being revealed, but research has discovered that hydroxymethylation is a part of oxidative DNA demethylation pathways. 5-hydroxymethylcytosine (5-hmC) is a modified form of cytosine believed to play a vital role in switching genes on and off. Ten-eleven translocation (TET) enzymes oxidize the methyl group of 5-methylcytosine (5-mC) and convert it to 5-hmC. TET enzymes are often deactivated or mutated in NPC.
Until now, 5-hmC has never been demonstrated to regulate the gene expression of a virus. However, as discussed in a recent blog article, researchers previously found that histone modifications controlled the reactivation of the herpes simplex virus in mice neurons, showing that other epigenetic mechanisms may be implicated in viral DNA expression. The Epstein-Barr virus is also known as human herpesvirus 4, which is considered a member of the herpes virus family.
Dr. Shannon Kenney, professor in the departments of oncology and medicine in the UW School of Medicine and Public Health, explained: “What we’ve discovered is that this modification can occur on the EBV genome and it affects how EBV is regulated. It’s important because this is the first virus where this modification has been shown to occur and regulate it.”
The researchers believe that infection by latent EBV plays a role in the formation of NPC later in its development, but lytic infection is required for tumor formation in early development of NPC because it enables the virus to spread. They investigated EBV-infected cells and demonstrated that a reduction of TET activity in these cells helps to switch the virus from latent to lytic so it can generate infectious viral particles. Specifically, by increasing cellular TET activity, they found a decrease in methylation and an increase in 5-hmC modification of lytic EBV promoters.
As much as 95 percent of adults actually have viral antibodies specific to EBV, suggesting they currently have an EBV infection or have had it in the past. In Dr. Kenney’s experience, patients with NPC have high levels of antibodies specific to EBV proteins that are only expressed when the virus is in its lytic form. To be expected, these patients had experienced a high-level lytic infection prior to developing NPC. Although most people are able to overcome an infection by EBV, it can be very dangerous to those whose immune systems are compromised or fighting serious infections.
“The cellular TET enzymes are increasingly recognized to be important for preventing a number of human cancers including glioblastoma, various types of leukemia and now perhaps EBV-induced NPC as well,” Kenney said. “That’s why we started to look and see if the loss of this modification on DNA is not only important for regulation of the cellular genes but also for what the EBV virus does in the cell. We know EBV is required for NPC, but this epigenetic modification really affects how the virus behaves.”
Source: Will, C.K., Nawandar, D.M., Henning, A.N., Ma, S., Oetting, K.M., Lee, D., Lambert, P., Johannsen, E.C., Kennet, S.C. (2015). 5-hydroxymethylation of the EBV genome regulates the latent to lytic switch. PNAS, 112(52): E7257-E7265.
Reference: School of Medicine and Public Health. DNA Changes Impacts Spread of Cancer-Causing Virus. University of Wisconsin-Madison. 1 Jan 2016. Web.