DNA ‘super-enhancers’ offer target for endometriosis treatment

Researchers have identified a potential genetic target for treating an especially painful and invasive form of endometriosis.

The findings could lead to better treatments for women suffering from severe forms of endometriosis, says Mike Wilson, a postdoctoral fellow in the College of Human Medicine at Michigan State University and first author of the paper in Cell Reports.

The researchers focused on a type of endometriosis that occurs in women who have a mutation in a gene called ARID1A, which is linked to the more invasive and painful form of the disease. When ARID1A is mutated, so-called “super-enhancers,” a part of the DNA that determines the function of cells, run wild, says coauthor Jake Reske, a graduate student in the Genetics and Genome Sciences Program.

This allows the cells that normally line the uterus to form deep implants outside the uterus and cause severe pelvic pain.

“There haven’t been many successful nonhormonal therapies for this form of endometriosis that have made it to the bedside yet,” Reske says.

In laboratory experiments, Reske and Wilson tested a drug that appeared to target the super-enhancers and stop the spread of endometriosis. Such a drug—part of a new type of treatment called “epigenetic therapy” that controls how genes are expressed—could be far more effective than current treatments, including surgery, hormone therapy, and pain management.

Endometriosis, particularly the kind associated with the ARID1A mutation, can prove debilitating for many women and often lead to infertility.

“It can seriously impact women’s quality of life and their ability to have a family and work,” says Ronald Chandler, an assistant professor of obstetrics, gynecology, and reproductive biology, who supervised the study.

“It’s not easy to treat, and it can become resistant to hormone therapy. The most clinically impactful thing we found is that targeting super-enhancers might be a new treatment for this deeply invasive form of the disease.”

The drug they studied targeted a protein in cells called P300, suppressing the super-enhancers and offsetting the effects of the ARID1A mutation, Wilson says. The same type of treatment could also treat other forms on endometriosis, he says.

The researchers say they plan follow-up studies to find other drugs that could target P300.

The researchers collaborated with Van Andel Institute scientists, providing them with tissue samples to analyze with a machine called a next-generation sequencer.

Source: Michigan State University

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