A new therapeutic route for the identified Epstein-Barr virus

Wistar Institute scientists say they have identified new potential routes for developing treatments that target the Epstein-Barr virus (EBV). They found that the way the EBV genome folds, thereby expressing itself and causing disease, is more complex than the researchers initially thought, and could be a target to break this fold. I have identified a molecule.

The team published the study (“The three-dimensional structure of the Epstein-Barr virus genome depends on the type of incubation period and is regulated by PARP1 enzyme activity.“) of Nature Communications..

“Epstein-Barr virus (EBV) survives in human B cells by maintaining its chromatinized episomes in the nucleus. Cell factor poly. [ADP-ribose] Polymerase 1 (PARP1) binds to the EBV genome, stabilizes CTCF binding at specific loci, and PARP1 enzyme activity correlates with the maintenance of a transcriptionally active latency program, “the researchers write.

“To better understand the role of PARP1 in the regulation of the EBV incubation period, we functionally characterize the effect of PARP enzyme inhibition on episomal structure through in situ HiC mapping and generate the complete 3D structure of the EBV genome. It also maps changes in intragenome contact after PARP inhibition to global binding of the chromatin loop factor CTCF to cohesin throughout the EBV genome. PARP inhibition reduces unique intragenome interactions within the EBV episome. However, a new chromatin loop that is different from the untreated episome is also formed.

“This study also shows that PARP inhibition alters gene expression in regions where chromatin loops are most affected. We find that PARP1 inhibition does not alter cohesin binding sites, but binding at those sites. Observe to increase the frequency.

“In summary, these findings indicate that PARP plays an essential role in the regulation of global EBV chromatin structure and potential gene expression.”

“We have identified two cellular proteins that are important for collapsing the EBV genome,” said Dr. Italo Tempera, an associate professor of gene expression and regulation programs at Wistar Institute and the corresponding author of the paper. I am saying. “There are existing drugs that target one of these proteins, and our data suggest that using that drug on EBV-infected cells can actually prevent folding. This means that the EBV viral genome can interfere with the way it works. “

Can change its gene expression

EBV, which affects more than 90% of individuals worldwide, is a dynamic virus, meaning that it can alter gene expression. When a particular viral gene is expressed, the virus infects B cells and causes them to overgrow. This is especially problematic for individuals with a depressed immune system, such as transplant patients.

Tempera and his colleagues wanted to understand the mechanism behind how the virus manipulates its gene expression. To do this, they used modified DNA sequencing techniques to investigate how the genome folds under a variety of conditions.

“It was wise for the virus to regulate its own gene expression using the same mechanisms that regulate the conformation of the human genome,” Tempera said. Specifically, we discovered that EBV uses two proteins, CTFC and PARP1. They are also involved in the expression of the human genome.

PARP1 has already been targeted by olaparib (sold under the Lynparza brand), which is used to treat patients with ovarian cancer. This new study suggests that the drug may also be used to treat EBV-positive lymphoma.

“Usually, PARP1 is targeted in the context of DNA damage,” Tempera explained. “Our paper shows that chromatin folding has another role for PARP1. Therefore, this not only prevents DNA damage, but also how to use this drug, which can prevent DNA folding. It suggests that it has the potential to expand. Gene expression. This is what we are currently testing in the lab. “