{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T22:39:36Z","timestamp":1785191976670,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Infertility is one of the most rapidly increasing global health concerns of the 21st century. Embryo quality and endometrial thickness and receptivity are the main factors for successful embryo implantation and pregnancy development. Nevertheless, until now, there has been a lack of understanding about the regulation of human endometrium function and its structure. This raises the demand for more research of the human endometrium in these fields. In our study, we analyzed the genetic and epigenetic changes of endometrial tissue\u2019s samples isolated from females admitted for treatment due to male infertility and females diagnosed with reproductive pathologies, who are preparing for assisted reproductive technologies procedures. Using real-time polymerase chain reaction method, we demonstrated that endometrium of females with reproductive pathology has significantly upregulated decidualization related genes HAND2, MUC1, CSF2, increased expression of angiogenesis related gene PDGFA, and increases of overall immune response and inflammation-related genes expression with significant changes of RELA and CXCL10 genes expression. Females with reproductive pathology have altered endometrium epigenetic regulation since expression of miRNAs\u2014specifically, miRNA-34a, miRNA-223, and miRNA-125b\u2014is lower in endometrium of females with reproductive pathology. Our findings suggest that the potential changes in genetic and epigenetic profile of endometrium from females with reproductive pathology could enrich the knowledge in the field of core biological knowledge and treatment of reproductive impairments.<\/jats:p>","DOI":"10.3390\/biomedicines10061324","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T09:42:32Z","timestamp":1654335752000},"page":"1324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Characterization of Epigenetic and Molecular Factors in Endometrium of Females with Infertility"],"prefix":"10.3390","volume":"10","author":[{"given":"Giedr\u0117","family":"Skliut\u0117","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Saul\u0117tekio Av. 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raminta","family":"Bau\u0161yt\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Saul\u0117tekio Av. 7, LT-10257 Vilnius, Lithuania"},{"name":"Centre of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Santari\u0161kiu\u02db St., LT-08661 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Rama\u0161auskait\u0117","sequence":"additional","affiliation":[{"name":"Centre of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Santari\u0161kiu\u02db St., LT-08661 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1077-9439","authenticated-orcid":false,"given":"R\u016bta","family":"Navakauskien\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Saul\u0117tekio Av. 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.mam.2012.12.011","article-title":"Physiological and molecular determinants of embryo implantation","volume":"34","author":"Zhang","year":"2013","journal-title":"Mol. Aspects Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12958-017-0309-7","article-title":"Role of MicroRNAs in embryo implantation","volume":"15","author":"Liang","year":"2017","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s10815-016-0773-6","article-title":"What Is the contribution of embryo-endometrial asynchrony to implantation failure?","volume":"33","author":"Teh","year":"2016","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.fertnstert.2019.02.009","article-title":"What exactly is endometrial receptivity?","volume":"111","author":"Lessey","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0950-3552(05)80092-6","article-title":"The implantation window","volume":"6","author":"Harper","year":"1992","journal-title":"Baillieres Clin. Obstet. Gynaecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/S0015-0282(16)54069-2","article-title":"The window of embryo transfer and the efficiency of human conception in vitro","volume":"55","author":"Navot","year":"1991","journal-title":"Fertil. Steril."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1210\/en.2017-03082","article-title":"Embryo implantation: War in times of love","volume":"159","author":"Ashary","year":"2018","journal-title":"Endocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1210\/er.2014-1045","article-title":"Cyclic decidualization of the human endometrium in reproductive health and failure","volume":"35","author":"Gellersen","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e73739","DOI":"10.7554\/eLife.73739","article-title":"Preparing for implantation","volume":"10","author":"Kim","year":"2021","journal-title":"eLife"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1002\/rmb2.12088","article-title":"Decidualization of the human endometrium","volume":"17","author":"Okada","year":"2018","journal-title":"Reprod. Med. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mrozikiewicz, A.E., O\u017carowski, M., and J\u0119drzejczak, P. (2021). Biomolecular markers of recurrent implantation failure\u2014A review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810082"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"g252","DOI":"10.1136\/bmj.g252","article-title":"Are we overusing IVF?","volume":"348","author":"Kamphuis","year":"2014","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.fertnstert.2020.11.014","article-title":"Top 10 priorities for future infertility research: An international consensus development study","volume":"115","author":"Duffy","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1053\/j.semperi.2017.07.001","article-title":"In vitro fertilization and adverse obstetric and perinatal outcomes","volume":"41","author":"Senapati","year":"2017","journal-title":"Semin. Perinatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12955-017-0712-y","article-title":"Quality of life and general health of infertile women","volume":"15","author":"Namdar","year":"2017","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.rbmo.2020.05.015","article-title":"Infertility remains a top stressor despite the COVID-19 pandemic","volume":"41","author":"Vaughan","year":"2020","journal-title":"Reprod. Biomed. Online"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaaf7533","DOI":"10.1126\/scitranslmed.aaf7533","article-title":"Loss of HDAC3 results in nonreceptive endometrium and female infertility","volume":"11","author":"Kim","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"578783","DOI":"10.3389\/fendo.2021.578783","article-title":"Effect of endometrium thickness on clinical outcomes in luteal phase short-acting GnRH-a long protocol and GnRH-ant protocol","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.rbmo.2019.02.013","article-title":"Management of thin endometrium in assisted reproduction: A clinical practice guideline from the Canadian fertility and andrology society","volume":"39","author":"Liu","year":"2019","journal-title":"Reprod. BioMed. Online"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2147\/IJWH.S165474","article-title":"Asherman\u2019s syndrome: Current perspectives on diagnosis and management","volume":"11","author":"Dreisler","year":"2019","journal-title":"Int. J. Womens Health"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/s41568-019-0177-x","article-title":"Clinical actionability of molecular targets in endometrial cancer","volume":"19","author":"Urick","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.beem.2006.03.005","article-title":"Endometrium in PCOS: Implantation and predisposition to endocrine CA","volume":"20","author":"Giudice","year":"2006","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1152\/physrev.00031.2019","article-title":"Physiology of the endometrium and regulation of menstruation","volume":"100","author":"Critchley","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ng, S.-W., Norwitz, G.A., Pavlicev, M., Tilburgs, T., Sim\u00f3n, C., and Norwitz, E.R. (2020). Endometrial decidualization: The primary driver of pregnancy health. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114092"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E433","DOI":"10.1210\/jc.2014-3720","article-title":"Decreased notch pathway signaling in the endometrium of women with endometriosis impairs decidualization","volume":"100","author":"Su","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9596","DOI":"10.1074\/jbc.RA120.012753","article-title":"The transcription factor HAND2 Up-regulates transcription of the IL15 gene in human endometrial stromal cells","volume":"295","author":"Murata","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.fertnstert.2012.08.056","article-title":"Progestin-induced heart and neural crest derivatives expressed transcript 2 is associated with Fibulin-1 expression in human endometrial stromal cells","volume":"99","author":"Cho","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Marquardt, R.M., Kim, T.H., Shin, J.-H., and Jeong, J.-W. (2019). Progesterone and estrogen signaling in the endometrium: What goes wrong in endometriosis?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153822"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1210\/me.2009-0448","article-title":"Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression","volume":"24","author":"Dharmaraj","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1177\/1933719108328609","article-title":"Mechanisms of leukocyte accumulation and activation in chorioamnionitis: Interleukin 1\u03b2 and tumor necrosis factor \u03b1 enhance colony stimulating factor 2 expression in term decidua","volume":"16","author":"Arcuri","year":"2009","journal-title":"Reprod. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10815-007-9152-7","article-title":"Angiogenesis in implantation","volume":"24","author":"Torry","year":"2007","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1038\/onc.2011.651","article-title":"MUC1 regulates PDGFA expression during pancreatic cancer progression","volume":"31","author":"Sahraei","year":"2012","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00441-012-1356-1","article-title":"Interaction of the conceptus and endometrium to establish pregnancy in mammals: Role of interleukin 1\u03b2","volume":"349","author":"Geisert","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.3389\/fimmu.2019.02896","article-title":"Human chorionic gonadotropin-mediated immune responses that facilitate embryo implantation and placentation","volume":"10","author":"Schumacher","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mahajan, D., Sharma, N.R., Kancharla, S., Kolli, P., Tripathy, A., Sharma, A.K., Singh, S., Kumar, S., Mohanty, A.K., and Jena, M.K. (2022). Role of natural killer cells during pregnancy and related complications. Biomolecules, 12.","DOI":"10.3390\/biom12010068"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sfakianoudis, K., Rapani, A., Grigoriadis, S., Pantou, A., Maziotis, E., Kokkini, G., Tsirligkani, C., Bolaris, S., Nikolettos, K., and Chronopoulou, M. (2021). The role of uterine natural killer cells on recurrent miscarriage and recurrent implantation failure: From pathophysiology to treatment. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101425"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13715","DOI":"10.1038\/s41598-021-93102-1","article-title":"Prokineticin 1\u2013prokineticin receptor 1 signaling in trophoblast promotes embryo implantation and placenta development","volume":"11","author":"Baryla","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Park, H., Cho, M., Do, Y., Park, J.-K., Bae, S.-J., Joo, J., and Ha, K.-T. (2021). Autophagy as a therapeutic target of natural products enhancing embryo implantation. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010053"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"728291","DOI":"10.3389\/fimmu.2021.728291","article-title":"Role of decidual natural killer cells in human pregnancy and related pregnancy complications","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/aji.12259","article-title":"Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis","volume":"72","author":"Giuliani","year":"2014","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/aji.12486","article-title":"Increased UNK progenitor cells in women with endometriosis and infertility are associated with low levels of endometrial stem cell factor","volume":"75","author":"Thiruchelvam","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13148-021-01103-8","article-title":"The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium","volume":"13","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.4161\/epi.26196","article-title":"MiR-34a expression, epigenetic regulation, and function in human placental diseases","volume":"9","author":"Doridot","year":"2014","journal-title":"Epigenetics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15605","DOI":"10.1038\/s41598-018-33807-y","article-title":"Characterization of the MiRNA regulators of the human ovulatory cascade","volume":"8","author":"Yerushalmi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9193236","DOI":"10.1155\/2019\/9193236","article-title":"Significant role of dicer and MiR-223 in adipose tissue of polycystic ovary syndrome patients","volume":"2019","author":"Qin","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sheikh, A.M., Small, H.Y., Currie, G., and Delles, C. (2016). Systematic review of micro-RNA expression in Pre-eclampsia identifies a number of common pathways associated with the disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160808"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"557.e1","DOI":"10.1016\/j.ajog.2020.02.050","article-title":"Accurate diagnosis of endometriosis using serum MicroRNAs","volume":"223","author":"Moustafa","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/21655979.2020.1736755","article-title":"Serum MiR-125b levels associated with epithelial ovarian cancer (EOC) development and treatment responses","volume":"11","author":"Chen","year":"2020","journal-title":"Bioengineered"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ceb.2012.03.009","article-title":"Bivalent histone modifications in early embryogenesis","volume":"24","author":"Vastenhouw","year":"2012","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1177\/1933719113497267","article-title":"Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications","volume":"21","author":"Monteiro","year":"2014","journal-title":"Reprod. Sci."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:24:36Z","timestamp":1760138676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,4]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biomedicines10061324"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10061324","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,4]]}}}