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In this study, we aimed to explore the relationship between<jats:italic>MEG3<\/jats:italic>and URSA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The differentially expressed lncRNAs (<jats:italic>MEG3<\/jats:italic>) and its downstream genes (<jats:italic>RASA1<\/jats:italic>) were identified using bioinformatics analysis of Genomic Spatial Event (GSE) database. The expression levels of<jats:italic>MEG3<\/jats:italic>in embryonic villis (with gestational ages of 49\u201363\u00a0days) and primary trophoblasts were determined using quantitative RT-PCR assay. A mouse model of Embryo implantation, Cell Counting Kit-8 (CCK-8), flow cytometry, and Transwell migration assays were performed to determine the implantation, proliferative, apoptotic, and invasive capacities of trophoblast. The level of phosphorylated core proteins in the RAS-MAPK pathway were analyzed using Western blot assay. The mechanisms of<jats:italic>MEG3<\/jats:italic>in the regulation of<jats:italic>RASA1<\/jats:italic>were studied by RNA pulldown, RNA immunoprecipitation (RIP), DNA pulldown, and chromatin immunoprecipitation (ChIP) assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>MEG3<\/jats:italic>had a low expression level in embryonic villis of 102 URSA patients compared with those of 102 normal pregnant women. MEG3 could promote proliferation and invasion, inhibit the apoptosis of primary trophoblast of URSA patients (PT-U cells), as well as promote embryo implantation of mouse. Besides, MEG3 also promoted the phosphorylation of rapidly accelerated fibrosarcoma (Raf), mitogen-activated protein kinase kinase (MEK), and extracellular-signal-regulated kinase (ERK) proteins. The results of RNA pull down and RIP assays showed that MEG3 bound with the enhancer of zeste homolog 2 (EZH2). The DNA pulldown assay revealed that MEG3 could bind to the promoter sequence of the RAS P21 Protein Activator 1 (<jats:italic>RASA1<\/jats:italic>) gene. Further, the ChIP assay showed that MEG3 promoted the binding of EZH2 to the promoter region of the<jats:italic>RASA1<\/jats:italic>gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The inactivation of MEG3 in embryonic villi association with URSA; MEG3 inhibited the expression of<jats:italic>RASA1<\/jats:italic>by mediating the histone methylation of the promoter of<jats:italic>RASA1<\/jats:italic>gene by EZH2, thereby activating the RAS-MAPK pathway and enhancing the proliferative and invasive capacities of trophoblasts.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s10020-021-00337-9","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T08:03:18Z","timestamp":1625731398000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion"],"prefix":"10.1186","volume":"27","author":[{"given":"Jun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinqiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8159-6496","authenticated-orcid":false,"given":"Yali","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"issue":"10","key":"337_CR1","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1080\/15476286.2018.1534524","volume":"15","author":"K Chanda","year":"2018","unstructured":"Chanda K, et al. 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