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(CACHET)"]}]},{"name":"Health Research Funds","award":["CP19\/00162"],"award-info":[{"award-number":["CP19\/00162"]}]},{"name":"Health Research Funds","award":["PI20\/00942"],"award-info":[{"award-number":["PI20\/00942"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1\/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a \u201chyper-inflammatory phenotype\u201d and an increased hormone-dependent risk of UFs later in life.<\/jats:p>","DOI":"10.3390\/ijms241411641","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T21:20:14Z","timestamp":1689801614000},"page":"11641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Epigenetic Modulation of Inflammatory Pathways in Myometrial Stem Cells and Risk of Uterine Fibroids"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-8946","authenticated-orcid":false,"given":"Qiwei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9675-6691","authenticated-orcid":false,"given":"Mohamed","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey S.","family":"Trevi\u00f1o","sequence":"additional","affiliation":[{"name":"Division of Health Equities, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5866-6732","authenticated-orcid":false,"given":"Aymara","family":"Mas","sequence":"additional","affiliation":[{"name":"INCLIVA Health Research Institute Avda, Men\u00e9ndez Pelayo 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahed","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-4447","authenticated-orcid":false,"given":"Ayman","family":"Al-Hendy","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1210\/endrev\/bnab039","article-title":"Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment","volume":"43","author":"Yang","year":"2022","journal-title":"Endocr. 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