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Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1\u03b2 is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1\/2 and CCAAT\/enhancer binding protein \u03b2 pathways. However, this amplification of ovulation by IL-1\u03b2 does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the effect of oxidative stress and IL-1\u03b2 expression on endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing (ChIP-Seq) of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1\u03b2-receptor that suppresses IL-1\u03b2-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1\u03b2 addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.<\/jats:p>","DOI":"10.1210\/endocr\/bqac210","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T13:12:11Z","timestamp":1671196331000},"source":"Crossref","is-referenced-by-count":12,"title":["Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2"],"prefix":"10.1210","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8183-1583","authenticated-orcid":false,"given":"Xiang","family":"Lin","sequence":"first","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Tong","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8353-9615","authenticated-orcid":false,"given":"Yinli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Gu","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianmeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , No. 109 Xueyuan WestRoad, Lucheng District, Wenzhou 325000 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanxuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Jin","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Li","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province , Shangcheng District, Hangzhou 310016 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Huang","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Shaw Hospital, Zhejiang University School of Medicine , Shangcheng District, Hangzhou 310016 , China"},{"name":"Key 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