Epigenetic regulatory mechanisms and therapeutic opportunities in endometriosis

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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.