Endometriosis, the pathologic endometrium-IIke tissue on pelvic organs, develops and persists in part due to defective apoptosis and is associated with pelvic pain and infertility. Our overall hypothesis is that defective steroid hormone and RA signaling is responsible for the abnormal reprogramming of endomethotic cells. We propose 3 aims. 1) To determine whether RORB deficiency, a consequence of progesterone resistance, is responsible for altered cell survival and differentiation in endometriosis. We uncovered a novel nuclear receptor (RORB), highly upregulated in response to progesterone in healthy cells, but absent in endometriotic cells. RORB regulates the differentiation of progenitor cells in the eye and in the bone in response to RA gradients, but has gone unnoticed in the endometrium. Our preliminary data suggest this progesterone-sensitive gene elicits the differentiation of endometrial stem cells in response to both progesterone and RA. We predict the loss of RORB in endometrial stem cells gives rise to diseased cells with altered differentiation and survival. We will determine the binding sites of RORB using CHIP-seq, and evaluate the in vivo and in vitro roles of RORB in healthy and diseased tissues to ascertain how progesterone and RA signaling coordinate biological changes in endometriosis. 2) To define the biological roles of key ER target genes in endometriosis. ER is one of the most significant targets affected by DNA methylation, and the loss of methylation across its promoter results in pathologic expression of ER and altered response to estrogen. Preliminary ChlP-seq and microarray studies identified the enzymes RERG and SGK1 as unique targets of ER, and suggested these genes mediate pro- inflammatory and pro-survival signaling in response to estrogen. We hypothesize the abnormal expression of these genes alters estrogen- and cell cycle-dependent gene expression and function. We will determine the molecular mechanism by which RERG and SGK1 contribute to the pathogenesis of endometriosis, as emerging therapies targeting these two enzymes would provide alternative treatment strategies for the disease. 3) To determine the mechanisms underlying steroid hormone and RA-dependent DNA methylation that are fundamental to endometriosis etiology. Our preliminary data identified large-scale differences in DNA methylation after the establishment of the disease. We hypothesize that key defects in methylation are already established or triggered in the eutopic endometrium of women destined to develop endometriosis. Using high throughput strategies to examine individual cells, this aim will examine the methylation status of key genes, and the body of enzymes that directly manipulate the methylation landscape in response to steroid hormones, RA and their nuclear receptors and focus on the DNMTs, which methylate DNA and the TETs, which demethylate DNA. The genome-wide effects of steroids and RA has not been well understood; however the unique epigenetic nature of endometriosis suggests that a genome-wide study of these enzymes will unveil the most critical targets that trigger the progression of the disease.
Five to ten million US women are estimated to suffer from endometriosis that causes pelvic pain and infertility. After standard treatments, symptoms usually recur within 6 months to 2 years; thus, there is a clear need for research. Here, we focus on mechanisms conferring resistance to natural death of endometriosis tissue due to specific deficiencies in steroid hormone and retinoic acid production and action. Uncovering molecular mechanisms underlying endometriosis may eventually lead to development of new therapeutic compounds that interact with novel targets. Unraveling the epigenetic origins of endometriosis may lead to the development of prevention strategies to lower the incidence of the disease in future generations.
|Bulun, Serdar E (2017) Steroids, Cytokines, and Implantation. Endocrinology 158:1575-1576|
|Monsivais, Diana; Dyson, Matthew T; Yin, Ping et al. (2016) Estrogen receptor ? regulates endometriotic cell survival through serum and glucocorticoid-regulated kinase activation. Fertil Steril 105:1266-1273|
|Pavone, Mary Ellen; Malpani, Saurabh S; Dyson, Matthew et al. (2016) Fenretinide: A Potential Treatment for Endometriosis. Reprod Sci 23:1139-47|
|Bulun, Serdar E; Nezhat, Camran (2016) Aromatase, microRNA, and inflammation: a complex relationship. Fertil Steril 106:552-3|
|Zhao, Hong; Zhou, Ling; Shangguan, Anna Junjie et al. (2016) Aromatase expression and regulation in breast and endometrial cancer. J Mol Endocrinol 57:R19-33|
|Moy, I; Todorovi?, V; Dubash, A D et al. (2015) Estrogen-dependent sushi domain containing 3 regulates cytoskeleton organization and migration in breast cancer cells. Oncogene 34:323-33|
|Dyson, Matthew T; Kakinuma, Toshiyuki; Pavone, Mary Ellen et al. (2015) Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil Steril 104:953-963.e2|
|Monsivais, D; Dyson, M T; Yin, P et al. (2014) ER?- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis. Mol Endocrinol 28:1304-15|
|Bulun, Serdar E (2014) Aromatase and estrogen receptor ? deficiency. Fertil Steril 101:323-9|
|Dyson, Matthew T; Roqueiro, Damian; Monsivais, Diana et al. (2014) Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet 10:e1004158|
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