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However, the downregulated ovary-elevated (OE) miRNAs and their biological functions in ovary remain elusive. Here, 13 downregulated OE miRNAs were systematically identified by integrating tissue expression high-throughput data and comparative transcriptome analyses, among which miR-184 was specifically highly expressed in ovary but dramatically downregulated during follicular atresia. Low miR-184 levels were also positively correlated with follicular atresia. Based on the in vitro GC and follicle culture system, we found that miR-184 suppressed GC apoptosis and follicular atresia. Mechanistically, miR-184 induced <jats:italic>SMAD3<\/jats:italic> transcription by acting as a saRNA, and also stabilized SMAD3 mRNA by directly binding to its 5\u2032-UTR, which promoted TGF-\u03b2 pathway activity and its anti-apoptotic effect. In addition, <jats:italic>miR-184<\/jats:italic> was transcribed independently of host gene, which was activated by SREBF2 in an H3K4me3-dependent manner. Comparative analysis revealed that SREBF2 expression and H3K4me3 enrichment on <jats:italic>miR-184<\/jats:italic> promoter in GCs from atretic follicles were dramatically reduced, which leads to the downregulation of miR-184 during follicular atresia. Moreover, the expression pattern, function, target, and regulatory mechanism of miR-184 among mammals are highly conserved and universal. Taken together, our findings demonstrate that miR-184, transcriptionally activated by SREBF2 in an H3K4me3-dependent manner, exerts anti-atretic effects by inducing <jats:italic>SMAD3<\/jats:italic> expression, highlighting that it is a promising regulator for improving follicular development, ovarian health and female fertility.<\/jats:p>","DOI":"10.1038\/s41419-024-07286-1","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T12:18:09Z","timestamp":1734524289000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["miR-184, a downregulated ovary-elevated miRNA transcriptionally activated by SREBF2, exerts anti-apoptotic properties in ovarian granulosa cells through inducing SMAD3 expression"],"prefix":"10.1038","volume":"15","author":[{"given":"Baosen","family":"Shan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangan","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhennan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengxiang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7985-3799","authenticated-orcid":false,"given":"Qifa","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-7803","authenticated-orcid":false,"given":"Xing","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"7286_CR1","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1093\/humrep\/dew066","volume":"31","author":"E Somigliana","year":"2016","unstructured":"Somigliana E, Paffoni A, Busnelli A, Filippi F, Pagliardini L, Vigano P, et al. 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