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Nuclear Receptor Signaling Atlas
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Identification of nuclear receptor genomic networks that link endometriosis to birth defects
Sang Jun Han
Baylor College of Medicine
Abstract
Endometrial cells can escape from the lining of the uterus and flourish in ectopic sites (named ectopic lesions), resulting in endometriosis, a pathology that results in severe pelvic pain and infertility in up to 5-10% of women. Previous studies suggested essential roles for Estrogen Receptors (ERs) in the progression of endometriosis because estrogen is considered a key driver in endometriosis pathogenesis. However, the roles of ERs in the progression of endometriosis are not yet elucidated. Notably, endometriotic tissues, such as endometriotic lesions and eutopic endometrium, have a much higher ratio of ERβ to ERα compared to the normal endometrium. In addition, our preliminary data revealed that the gain of ERβ function stimulates ectopic lesion growth in mice with endometriosis. Therefore, these data strongly support an essential role for ERβ in the pathogenesis of endometriosis. As endometriosis is known to be an estrogen-dependent inflammatory disease, endometriosis is correlated with the pathogenesis of other women’s reproductive diseases. For example, the association between endometriosis and infertility is well supported throughout the literature. However, a definite cause-effect relationship between endometriosis and infertility is not yet described. Interestingly, elevated ERβ expression levels are also detected in the eutopic endometrium of humans and mice with endometriosis, in addition to ectopic lesions. Our novel ERβ-overexpressing mice, which have elevated levels of flag-tagged human ERβ in endometrial tissues, revealed that endometrium-specific ERβ overexpression causes infertility in mice due to loss of the decidualization process in the endometrium. In addition to the mouse endometrium, ERβ-overexpressing human endometrial stromal cells also did not differentiate into decidual cells upon exposure to a cocktail of steroid hormones and cAMP treatment for in vitro decidualization. Therefore, the gain of ERβ function causes endometrial dysfunction, leading to infertility. However, the molecular mechanisms behind the role of ERβ during the progression of endometriosis and the development of endometriosis-associated infertility have not yet been elucidated.

The overall goal of this proposal is to first generate a global “omics” level profile of ERβ function in endometriotic lesions and eutopic endometrium using a mouse model of endometriosis. Therefore, this project should advance our understanding of how ectopic and eutopic endometrial ERβ signaling cooperatively modulates the progression of endometriotic lesions and the development of endometriosis-associated infertility. To accomplish this project, we have two specific aims:

Specific Aim 1. To determine and validate the direct ERβ target gene signature in ectopic lesions that is required for their growth.

Specific Aim 2. To define and validate the direct ERβ target gene signature in the eutopic endometrium of mice with endometriosis that is involved in endometriosis-associated infertility.

To generate the specific transcriptome of endometriotic tissues, such as ectopic lesions and eutopic endometrium, RNA-Seq analyses will be conducted using ectopic lesions and eutopic endometrium of ERβ- overexpressing mice with surgically induced endometriosis compared to sham-treated uterus of control mice. To determine the endometriotic tissue-specific ERβ cistrome, ERβ ChIP-Seq will be performed with a Flag antibody, and the Flag ChIP-Seq of ectopic lesions and eutopic endometrium isolated from ERβ- overexpressing mice with endometriosis will be compared to the endometriotic tissues of control mice with endometriosis. Finally, to address each specific aim, we will integrate the transcriptome and ERβ-regulated cistrome to generate ectopic lesion- and eutopic endometrium-specific direct ERβ target gene signatures that have essential roles in endometriotic lesion growth and endometriosis-associated infertility. These ERβ-directed gene signatures could be employed as an alternative treatment option that may help reduce the side effects of the current endometriosis treatment options and improve the fecundity of women with endometriosis.