{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T07:35:28Z","timestamp":1771572928907,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,11]],"date-time":"2021-12-11T00:00:00Z","timestamp":1639180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003336","name":"Bulgarian Science Fund","doi-asserted-by":"publisher","award":["\u041a\u041f-06 \u041d31\/2"],"award-info":[{"award-number":["\u041a\u041f-06 \u041d31\/2"]}],"id":[{"id":"10.13039\/501100003336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PRG1076"],"award-info":[{"award-number":["PRG1076"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Horizon 2020 innovation grant of the European Commission.","award":["ERIN, grant no. EU952516"],"award-info":[{"award-number":["ERIN, grant no. EU952516"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Embryo implantation depends on endometrial receptivity (ER). To achieve ER, the preparation of the uterine lining requires controlled priming by ovarian hormones and the expression of numerous genes in the endometrial tissue. microRNAs (miRs) have emerged as critical genetic regulators of ER in fertility and of the diseases that are associated with infertility. With the rapid development of next-generation sequencing technologies, it has become clear that miR genes can produce canonical miRs and variants\u2014isomiRs. Here, we describe miR\/isomiR expression dynamics across the four time points of natural chorionic gonadotropin (hCG)-administered cycles. Sequencing of the small RNAs (sRNA-seq) revealed that the most significant expression changes during the transition from the pre-receptive to the receptive phase occurred in the isomiR families of miR-125a, miR-125b, miR-10a, miR-10b, miR-449c, miR-92a, miR-92b, and miR-99a. Pairing the analysis of the differentially expressed (DE) miRs\/isomiRs and their predicted DE mRNA targets uncovered 280 negatively correlating pairs. In the receptive endometrium, the 5\u20323\u2032-isomiRs of miR-449c, which were among the most highly up-regulated isomiRs, showed a negative correlation with their target, transcription factor (TF) MYCN, which was down-regulated. Joint analysis of the miR\/isomiR and TF expression identified several regulatory interactions. Based on these data, a regulatory TF-miR\/isomiR gene-target circuit including let7g-5p and miR-345; the isomiR families of miR-10a, miR-10b, miR-92a, and miR-449c; and MYCN and TWIST1 was proposed to play a key role in the establishment of ER. Our work uncovers the complexity and dynamics of the endometrial isomiRs that can act cooperatively with miRs to control the functionally important genes that are critical to ER. Further studies of miR\/isomiR expression patterns that are paired with those of their target mRNAs may provide a more in-depth picture of the endometrial pathologies that are associated with implantation failure.<\/jats:p>","DOI":"10.3390\/life11121391","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:29:33Z","timestamp":1639358973000},"page":"1391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Coupling miR\/isomiR and mRNA Expression Signatures Unveils New Molecular Layers of Endometrial Receptivity"],"prefix":"10.3390","volume":"11","author":[{"given":"Maria","family":"Nikolova","sequence":"first","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"},{"name":"Center for Women\u2019s Health, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mladen","family":"Naydenov","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilias","family":"Glogovitis","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"},{"name":"Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apostol","family":"Apostolov","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merli","family":"Saare","sequence":"additional","affiliation":[{"name":"Competence Centre on Health Technologies, 50411 Tartu, Estonia"},{"name":"Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8588-8445","authenticated-orcid":false,"given":"Nageswara","family":"Boggavarapu","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Karolinska Institute, 17177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1251-8160","authenticated-orcid":false,"given":"Andres","family":"Salumets","sequence":"additional","affiliation":[{"name":"Competence Centre on Health Technologies, 50411 Tartu, Estonia"},{"name":"Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia"},{"name":"Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, 17177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5224-9145","authenticated-orcid":false,"given":"Vesselin","family":"Baev","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galina","family":"Yahubyan","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Plovdiv, Plovdiv, Bulgaria; Tzar Assen 24, 4000 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1126\/science.1065329","article-title":"An Extensive Class of Small RNAs in Caenorhabditis Elegans","volume":"294","author":"Lee","year":"2001","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1126\/science.1064921","article-title":"Identification of Novel Genes Coding for Small Expressed RNAs","volume":"294","author":"Rauhut","year":"2001","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1101\/gr.2722704","article-title":"Identification of Mammalian MicroRNA Host Genes and Transcription Units","volume":"14","author":"Rodriguez","year":"2004","journal-title":"Genome Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ha, M., and Kim, V.N. 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