{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T18:17:17Z","timestamp":1785867437131,"version":"3.56.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>The N6-methyladenosine (m<jats:sup>6<\/jats:sup>A) RNA modification regulates the expression of genes associated with various biological and pathological processes, including spontaneous abortion (SA). The aim of this study was to determine the role of the m<jats:sup>6<\/jats:sup>A demethylase fat mass and obesity (FTO)- associated protein in SA. The <jats:italic>FTO<\/jats:italic>,<jats:italic>IGF2BP1<\/jats:italic> and <jats:italic>IGF2BP2<\/jats:italic> mRNA levels were significantly lower in the chorionic villi obtained from spontaneously aborted pregnancies compared to that of normal pregnancies, while the expression levels of <jats:italic>METTL3<\/jats:italic> and <jats:italic>WTAP<\/jats:italic> were significantly elevated. However, <jats:italic>ALKBH5<\/jats:italic>, <jats:italic>YTHDF2<\/jats:italic>, and <jats:italic>IGF2BP3<\/jats:italic> were elevated with no statistical significance between groups. In addition, MDA was elevated and SOD levels were decreased in the villi tissues of the SA group compared to the normal group, which was indicative of placental oxidative stress in the former. Furthermore, the expression of FTO and HLA-G were significantly decreased in the trophoblasts of the SA patients compared to that of normal pregnant women, while that of m<jats:sup>6<\/jats:sup>A was markedly higher in the former. In addition, the <jats:italic>HLA-G<\/jats:italic> and <jats:italic>VEGFR<\/jats:italic> mRNA levels were downregulated in the SA versus the control group, and that of <jats:italic>MMP2<\/jats:italic>, <jats:italic>MMP7<\/jats:italic>, <jats:italic>MMP9<\/jats:italic> and <jats:italic>VEGFA<\/jats:italic> were upregulated. Finally, The RIP assay showed significantly decreased levels of FTO-bound <jats:italic>HLA-G<\/jats:italic>, <jats:italic>VEGFR<\/jats:italic> and <jats:italic>MMP9<\/jats:italic> RNA in SA patients (<jats:italic>P<\/jats:italic> &amp;lt; 0.05), which corresponded to an increase in transcripts enriched with the m<jats:sup>6<\/jats:sup>A antibody (<jats:italic>P<\/jats:italic> &amp;lt; 0.05). However, compared with normal pregnant women, the levels of <jats:italic>HLA-G<\/jats:italic>, <jats:italic>VEGFA<\/jats:italic>, <jats:italic>VEGFR<\/jats:italic>, and <jats:italic>MMP2<\/jats:italic> mRNA bound by YTHDF2 were significantly decreased in SA patients. Compared to the normal pregnant women, both FTO- and m<jats:sup>6<\/jats:sup>A-bound <jats:italic>MMP7<\/jats:italic> were significantly increased in SA patients (<jats:italic>P<\/jats:italic> &amp;lt; 0.05), but YTHDF2 almost unbound to <jats:italic>MMP7<\/jats:italic> mRNA. In summary, the downregulation of FTO in the chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, resulting in aberrant methylation and oxidative stress that eventually leads to SA.<\/jats:p>","DOI":"10.3389\/fcell.2021.617172","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:59:48Z","timestamp":1626674388000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":47,"title":["RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion"],"prefix":"10.3389","volume":"9","author":[{"given":"Weiyu","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxing","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingying","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songping","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1111\/aogs.12640","article-title":"The obesity-related FTO gene variant associates with the risk of recurrent miscarriage.","volume":"94","author":"Andraweera","year":"2015","journal-title":"Acta Obstet. Gynecol. Scand"},{"key":"B2","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.mehy.2011.02.017","article-title":"HLA-G and pregnancy adverse outcomes.","volume":"76","author":"Cecati","year":"2011","journal-title":"Med. Hypotheses"},{"key":"B3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s10529-018-2632-2","article-title":"Improved yield of rhEPO in CHO cells with synthetic 5\u2019 UTR.","volume":"41","author":"Costello","year":"2019","journal-title":"Biotechnol. Lett"},{"key":"B4","doi-asserted-by":"publisher","first-page":"20117","DOI":"10.1016\/S0021-9258(17)30477-5","article-title":"Sequence specificity of mRNA N6-adenosine methyltransferase.","volume":"265","author":"Csepany","year":"1990","journal-title":"J. Biol. Chem"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1515\/CCLM.2009.311","article-title":"Biochemical role of intravaginal sildenafil citrate as a novel antiabortive agent in unexplained recurrent spontaneous miscarriage: first clinical study of four case reports from Egypt.","volume":"47","author":"El-Far","year":"2009","journal-title":"Clin. Chem. Lab. Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1515\/CCLM.2007.138","article-title":"Tumor necrosis factor-\u03b1 and oxidant status are essential participating factors in unexplained recurrent spontaneous abortions.","volume":"45","author":"El-Far","year":"2007","journal-title":"Clin. Chem. Lab. Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1071\/RD17117","article-title":"Angiogenesis and oxidative stress-related gene variants in recurrent pregnancy loss.","volume":"30","author":"Fortis","year":"2018","journal-title":"Reprod. Fertil. Dev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1126\/science.1151710","article-title":"The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.","volume":"318","author":"Gerken","year":"2007","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1093\/humupd\/dmz042","article-title":"Identifying biomarkers for predicting successful embryo implantation: applying single to multi-OMICs to improve reproductive outcomes.","volume":"26","author":"Hern\u00e1ndez-Vargas","year":"2020","journal-title":"Hum. Reprod. Update"},{"key":"B10","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.ccell.2020.02.004","article-title":"m6 A Modification in Coding and Non-coding RNAs: roles and Therapeutic Implications in Cancer.","volume":"37","author":"Huang","year":"2020","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41556-018-0045-z","article-title":"Recognition of RNA N-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.","volume":"20","author":"Huang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S0002-9440(10)63803-5","article-title":"Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.","volume":"162","author":"Jauniaux","year":"2003","journal-title":"Am. J. Surg. Pathol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nchembio.687","article-title":"N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.","volume":"7","author":"Jia","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201800134","article-title":"Diet during pregnancy is implicated in the regulation of hypothalamic RNA methylation and risk of obesity in offspring.","volume":"62","author":"Kaspi","year":"2018","journal-title":"Mol. Nutr. Food Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1158\/0008-5472.CAN-18-2965","article-title":"The critical role of RNA m6A methylation in cancer.","volume":"79","author":"Lan","year":"2019","journal-title":"Cancer Res"},{"key":"B16","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.tig.2019.12.007","article-title":"Molecular Mechanisms Driving mRNA Degradation by mA Modification.","volume":"36","author":"Lee","year":"2020","journal-title":"Trends Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.bbagrm.2018.10.014","article-title":"Mechanistic insights into m6A RNA enzymes.","volume":"1862","author":"Lence","year":"2019","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.7150\/thno.31868","article-title":"The m6A demethylase ALKBH5 controls trophoblast invasion at the maternal-fetal interface by regulating the stability of CYR61 mRNA.","volume":"9","author":"Li","year":"2019","journal-title":"Theranostics"},{"key":"B19","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1161\/CIRCULATIONAHA.118.033794","article-title":"FTO-dependent N6-methyladenosine regulates cardiac function during remodeling and repair.","volume":"139","author":"Mathiyalagan","year":"2019","journal-title":"Circulation"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.17219\/acem\/74653","article-title":"Circulating parameters of oxidative stress and hypoxia in normal pregnancy and HELLP syndrome.","volume":"27","author":"Mentese","year":"2018","journal-title":"Adv. Clin. Exp. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"143.e9","DOI":"10.1016\/j.neurobiolaging.2020.03.018","article-title":"Genetic analysis of N6-methyladenosine modification genes in Parkinson\u2019s disease.","volume":"93","author":"Qin","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.10.022","article-title":"Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders.","author":"Rana","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20200613","article-title":"Regulation of miR-375 and Sonic hedgehog on vascular endothelial growth factor in preeclampsia rats and its effect on trophoblast cells.","author":"Ren","year":"2020","journal-title":"Biosci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1080\/ejc.6.3.141.144","article-title":"Randomized outpatient clinical trial of medical evacuation and surgical curettage in incomplete miscarriage.","volume":"6","author":"Sahin","year":"2001","journal-title":"Eur. J. Contracept. Reprod. Health Care"},{"key":"B25","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.molcel.2019.04.025","article-title":"Where, When, and How: context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers.","volume":"74","author":"Shi","year":"2019","journal-title":"Mol. Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"S762","DOI":"10.1016\/j.ajog.2017.11.567","article-title":"Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?.","volume":"218","author":"Sultana","year":"2018","journal-title":"Am. J. Obstet. Gynecol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2020.103264","article-title":"Functional Regulation of Decidual Macrophages during Pregnancy.","volume":"143","author":"Sun","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1089\/ars.2019.7891","article-title":"The potent antioxidant MitoQ protects against preeclampsia during late gestation but increases the risk of preeclampsia when administered in early pregnancy.","volume":"34","author":"Yang","year":"2021","journal-title":"Antioxid. Redox Signal"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2020.113911","article-title":"Increased m6A RNA modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury.","volume":"259","author":"Zhao","year":"2020","journal-title":"Environ. Pollut"},{"key":"B30","doi-asserted-by":"publisher","first-page":"7948","DOI":"10.1002\/jcp.28014","article-title":"A dynamic reversible RNA N -methyladenosine modification: current status and perspectives.","volume":"234","author":"Zhen","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1016\/j.molcel.2018.01.019","article-title":"N6-methyladenosine guides mRNA alternative translation during integrated stress response.","volume":"69","author":"Zhou","year":"2018","journal-title":"Mol. Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.617172\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:59:50Z","timestamp":1626674390000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.617172\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,19]]},"references-count":31,"alternative-id":["10.3389\/fcell.2021.617172"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.617172","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,19]]},"article-number":"617172"}}