Epigenetic regulatory mechanisms and therapeutic opportunities in endometriosis

Project Summary
Endometriosis affects 1 in 10 women of reproductive age and is associated with chronic pelvic pain and
infertility. The disease is characterized by the presence of abnormal endometrial tissue at sites outside the
uterus. Current treatment options for endometriosis are limited to surgery, hormone therapy and pain
management. There is an unmet need for non-hormonal treatment options that specifically target abnormal
endometrial tissue. Retrograde menstruation promotes the spread of endometrial tissue from the uterus to
ectopic sites within the peritoneal cavity. Although retrograde menstruation plays a role in the establishment of
the disease, additional factors are necessary for endometriosis development. Understanding how displaced
endometrial cells cause the disease requires an understanding of the molecular mechanisms that allow
endometrial cells to invade, survive and colonize ectopic sites. The recent identification of recurrent ARID1A
mutations in endometriotic lesions supports a causal role for epigenetic dysregulation in endometriosis
development. We hypothesize that epigenetic dysregulation predisposes displaced endometrial cells to
endometriosis by promoting the aberrant expression of genes and pathways necessary for endometrial cell
invasion and survival. In this study, we will utilize innovative model systems and advanced `omics technologies
to investigate the role of the genome, epigenome and transcriptome in endometriosis development and inform
new prevention and treatment strategies. In Aim 1, we will determine the mechanism by which histone
acetyltransferase activity and histone acetylation promotes endometrial invasion and survival. We will provide
rationale for histone acetyltransferase inhibition as a potential non-hormonal therapeutic strategy for women
with endometriosis. In Aim 2, we will address the role of variant histone exchange in endometriosis
development. Our primary objectives are to uncover the epigenetic regulatory mechanisms that lead to
endometriosis and find new ways to therapeutically target abnormal endometrial cells by leveraging
vulnerabilities that arise from epigenetic alterations in the disease. Our aspirational goals are to identify new
ways to definitively diagnose, prevent and treat endometriosis.

Grant Number: 5R01HD103617-05
NIH Institute/Center: NIH
Principal Investigator: Ronald Chandler