Epigenetic therapy attracting attention as a treatment for endometriosis

Scientists based at Michigan State University (MSU) report that they can treat particularly painful and invasive endometriosis retrospectively. To demonstrate this possibility, scientists have pharmacologically inhibited P300, a protein involved in the dysregulation of endometrial epithelial cells that normally line the uterus.

In severe endometriosis, P300 has relatively free access to the super enhancer, the genetic component that determines cell function. Upon exposure to P300, super enhancers, especially those associated with SERPINE1 (PAI-1), are overactivated and stimulate endometrial epithelial cells to proliferate, diffuse and form deep extrauterine implants. , Causes severe pelvic pain.

This series of events occurs in the absence of the ARID1A protein, due to a mutation in the ARID1A gene. Normally, the ARID1A protein co-localizes with super enhancers, restricting access by P300 and preventing hyperacetylation. To make up for the lack of ARID1A, the MSU team chose the appropriate solution, suppression of P300.

Details of this work were published in the journal on November 10th. Cell reports, “ARID1A mutation promotes P300-dependent endometrial infiltration through hyperacetylation of super enhancers.. “

“To identify epigenetic dependencies that promote invasion, we use an unbiased approach to map chromatin state transitions associated with loss of ARID1A in the endometrium,” the article author wrote. I will. “The loss of ARID1A leads to overacetylation of H3K27 and increased chromatin accessibility and enhancer RNA transcription in the super enhancer, but ARID1A, rather than the typical enhancer, usually overactivates the super enhancer. Indicates to prevent.

“ARID1A is a super enhancer and co-localizes with P300, and genetic or pharmacological inhibition of P300 in the ARID1A mutant endometrial epithelium suppresses infiltration through the relief of super enhancer hyperacetylation and induces anoikiss. Among the hyper-activated super enhancers, SERPINE1 (PAI-1) has been identified as an essential target gene that promotes endometrial infiltration of ARID1A mutants. “

The lead author of this study, Mike Wilson, Ph.D. Jake Reske said that inhibition of P300 could lead to better treatment for women suffering from severe endometriosis associated with mutant ARID1A. (Wilson is a postdoctoral fellow at Michi Human Medicine University and Reske is a graduate student in the MSU Genetics and Genomics Program.) “Non-hormone therapy for this form of endometriosis has been less successful,” Reske said. Added.

In laboratory experiments, Wilson and Reske demonstrated that P300 inhibition in ARID1A mutant cells suppresses infiltration and induces anoikis, a form of programmed cell death. P300 is a type of epigenetic drug. In other words, it controls how genes are expressed. The MSU team suggests that P300 may be far more effective than current therapies such as surgery, hormone therapy, and pain management.

Endometriosis, especially those associated with the ARID1A mutation, can be debilitating for many women and often leads to infertility.

“It can have a serious impact on women’s quality of life and their ability to work with their families and work,” said Dr. Ronald Chandler, an assistant professor of obstetrics, gynecology and reproductive biology who oversaw the study. It was. “Treatment is not easy and can be resistant to hormone therapy. The most clinically influential thing we have found is that targeting super enhancers is this deeply invasive form. It may be a new treatment for the disease. “

Chandler and colleagues are already planning a follow-up study to find other epigenetic drugs that may target P300. Chandler says the epigenetic approach can be used to treat other forms of endometriosis.