Date of Award


Degree Name

Biomedical Sciences


Joan C. Edwards School of Medicine

Type of Degree


Document Type


First Advisor

Dr. Nalini Santanam, Committee Chairperson

Second Advisor

Dr. Richard Egleton

Third Advisor

Dr. Travis Salisbury

Fourth Advisor

Dr. Elaine Hardman

Fifth Advisor

Dr. Elsa Mangiarua


Endometriosis is a complex and elusive gynecological disease in which the inner lining of the uterus grows in locations outside of the uterus and forms lesions. It is known to affect 1 in 9 women of reproductive age worldwide. Symptoms of endometriosis include severe pain, heavy periods, and infertility. While multiple theories of origin exist, none fully encompass all aspects of the disease, although all theories agree that this is an inflammation-driven disease. Due to this, many researchers are turning towards epigenetics to explain the initiation and progression of endometriosis. However, what is causing these epigenetic changes is still a mystery. We hypothesize that peritoneal fluid (PF) from women with endometriosis, full of chemokines, cytokines, and inflammatory molecules, is the initiator behind the changes seen, specifically the Polycomb repressive complex 2 (PRC2) and its catalytic subunit Enhancer of zeste homolog 2 (EZH2). We noted that there was an upregulation of the PRC2 complex and EZH2 in tissue from women with endometriosis. This upregulation was also seen when endometrial cells were treated with PF from women with endometriosis. miR-155 was also shown to be upregulated in the endometrial lesions and endo PF treated cells examined. Interactions between EZH2 and other genes that may be mechanistically working in the pathogenesis of endometriosis were seen through the use of ChIP-qPCR. The results of this study showed us that the PF from women with endometriosis is playing a role in initiating epigenetic mechanisms as well as providing us a potential novel cross-talk between miR-155 and the PRC2 complex. We used the results of upregulation of EZH2 due to PF from women with endometriosis and examined whether these changes could be inhibited or reversed through targeting an inflammatory pathway, the CXCR4- CXCL12-CXCR7 axis, in endometriosis through the use of a CXCR4 agonist AMD3100. We also examined if the EZH2 inhibitor GSK126 would target this inflammatory pathway. Both cells and tissues from women without endometriosis were treated with a combination of control or endo PF and/or AMD3100 or GSK126 in order to examine gene expression as well as changes in cell proliferation and migration. Endometrial PF was shown to increase the expression of EZH2, as well as the proliferation of the cells. When AMD3100 or GSK126 was added to the cells and the tissues in the presence of endometriosis PF, dual results were noted, suggesting that a one-sided approach, targeting just the inflammation or just the epigenetic mechanisms is not the correct approach for treatment. The best alteration of gene expression, suppression of cell proliferation, and suppression of migration was noted when combining the two compounds for a dual-sided treatment. Overall, the studies presented in this thesis show that both epigenetic mechanisms and inflammatory pathways drive the progression of endometriosis. Further studies will examine the effects that the compounds used in these studies have in animal models of endometriosis where lesion growth and pain levels will be observed.


Endometriosis -- Research.

DNA -- Methylation -- Research.