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- Title
- ARID1A MUTANT PATHOGENESIS OF THE ENDOMETRIAL EPITHELIUM
- Creator
- Reske, Jake Jordan
- Date
- 2021
- Collection
- Electronic Theses & Dissertations
- Description
-
Women’s health diseases represent an understudied, widespread medical concern with historically limited treatment options. Diseases of the endometrium, the innermost lining of the uterus, are a highly prevalent public burden. Endometriosis occurs in 1 in 10 women, and endometrial cancer is the most common gynecologic malignancy in the United States. Recent advances have revealed recurrent genetic causes of endometrial diseases, including gene mutations known to play a role in cancer...
Show moreWomen’s health diseases represent an understudied, widespread medical concern with historically limited treatment options. Diseases of the endometrium, the innermost lining of the uterus, are a highly prevalent public burden. Endometriosis occurs in 1 in 10 women, and endometrial cancer is the most common gynecologic malignancy in the United States. Recent advances have revealed recurrent genetic causes of endometrial diseases, including gene mutations known to play a role in cancer development. ARID1A is one such gene that is commonly mutated in endometrial diseases, and it encodes a protein involved in regulating DNA packaging and activity in the cell nucleus within a large complex known as SWI/SNF. The focus of this dissertation is to improve our understanding of how ARID1A mutations promote endometrial diseases at multiple biological levels, with a particular focus on how disrupted chromatin regulation affects physiologically relevant gene expression. In these works, genetic engineering techniques are leveraged in mice and human cell-based models supported by public and clinical data to establish the consequences of ARID1A mutations in the endometrium and how they relate to other common genetic alterations in these diseases. These studies have revealed that ARID1A is a tumor suppressor in the endometrial epithelium, such that ARID1A loss drives cellular invasion into nearby tissue. ARID1A mutations also promote invasive metastasis and squamous metaplasia in the context of aggressive TP53 mutations. At the level of chromatin, ARID1A and SWI/SNF directly regulate endometrial epithelial identity genes through both promoter and distal enhancer chromatin interactions. Mechanistically, ARID1A mutant invasion is driven by cell identity control regions known as super-enhancers that become hyperactivated, which can be reversed pharmacologically. Moreover, ARID1A physically and genomically interacts with other nuclear chromatin regulators to govern gene activation states through variant histone regulation. These works have contributed in multiple aspects toward deciphering how ARID1A mutations promote disease in the endometrium, including pre-clinical support for using epigenetic therapies to treat invasive ARID1A mutant endometrial conditions. Future efforts will aim to further identify and understand molecular and biochemical mechanisms linking ARID1A and SWI/SNF chromatin remodeling activity to regulation of gene expression. Ongoing work seeks to explain roles of ARID1A and SWI/SNF epigenetic regulation in normal physiological processes of the endometrium, such as hormone signaling across the menstrual cycle.
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