{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:40Z","timestamp":1792789300037,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Italian Ministry of University","award":["2017S9KTNE"],"award-info":[{"award-number":["2017S9KTNE"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Telomeres are considered to be an internal biological clock, and their progressive shortening has been associated with the risk of age-related diseases and reproductive alterations. Over recent years, an increasing number of studies have focused on the association between telomere length and fertility, identifying sperm telomere length (STL) as a novel biomarker of male fertility. Although typically considered to be repeated DNA sequences, telomeres have recently been shown to also include a long non-coding RNA (lncRNA) known as TERRA (telomeric repeat-containing RNAs). Interestingly, males with idiopathic infertility show reduced testicular TERRA expression, suggesting a link between TERRA and male fertility. The aim of this study was to investigate the role of seminal TERRA expression in embryo quality. To this end, STL and TERRA expression were quantified by Real Time qPCR in the semen of 35 men who underwent assisted reproductive technologies (ART) and 30 fertile men. We found that TERRA expression in semen and STL was reduced in patients that underwent ART (both p &lt; 0.001). Interestingly, TERRA and STL expressions were positively correlated (p = 0.010), and TERRA expression was positively associated with embryo quality (p &lt; 0.001). These preliminary findings suggest a role for TERRA in the maintenance of sperm telomere integrity during gametogenesis, and for the first time, TERRA expression was found as a predictive factor for embryo quality in the setting of assisted reproduction.<\/jats:p>","DOI":"10.3390\/genes12040475","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T14:51:12Z","timestamp":1616683872000},"page":"475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["TERRA: A Novel Biomarker of Embryo Quality and Art Outcome"],"prefix":"10.3390","volume":"12","author":[{"given":"Maria Santa","family":"Rocca","sequence":"first","affiliation":[{"name":"Department of Medicine, University Hospital of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Dusi","sequence":"additional","affiliation":[{"name":"GENERA Veneto, GENERA Center for Reproductive Medicine, 36063 Marostica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Di Nisio","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospital of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3390-1211","authenticated-orcid":false,"given":"Erminia","family":"Alviggi","sequence":"additional","affiliation":[{"name":"Clinica Ruesch, GENERA Center for Reproductive Medicine, 80122 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Iussig","sequence":"additional","affiliation":[{"name":"GENERA Veneto, GENERA Center for Reproductive Medicine, 36063 Marostica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bertelle","sequence":"additional","affiliation":[{"name":"GENERA Veneto, GENERA Center for Reproductive Medicine, 36063 Marostica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"De Toni","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospital of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4736-9051","authenticated-orcid":false,"given":"Andrea","family":"Garolla","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospital of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6576-2183","authenticated-orcid":false,"given":"Carlo","family":"Foresta","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospital of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5817-8141","authenticated-orcid":false,"given":"Alberto","family":"Ferlin","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, Unit of Endocrinology and Metabolism, University of Brescia and ASST Spedali Civili Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of male infertility","volume":"15","author":"Krausz","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_2","first-page":"203","article-title":"The X chromosome and male infertility","volume":"140","author":"Vockel","year":"2021","journal-title":"Qual. Life Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ferlin, A., and Foresta, C. (2020). Infertility: Practical Clinical Issues for Routine Investigation of the Male Partner. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061644"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/humrep\/16.8.1768","article-title":"Contribution of environmental factors to the risk of male infertility","volume":"16","author":"Oliva","year":"2001","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.aju.2017.12.004","article-title":"Lifestyle causes of male infertility","volume":"16","author":"Durairajanayagam","year":"2018","journal-title":"Arab. J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.reprotox.2006.04.016","article-title":"Genetic causes of male infertility","volume":"22","author":"Ferlin","year":"2006","journal-title":"Reprod. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.euf.2019.08.001","article-title":"Sperm Count and Hypogonadism as Markers of General Male Health","volume":"7","author":"Ferlin","year":"2021","journal-title":"Eur. Urol. Focus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1101\/gad.263863.115","article-title":"Human telomerase: Biogenesis, trafficking, recruitment, and activation","volume":"29","author":"Schmidt","year":"2015","journal-title":"Genes Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1128\/MMBR.66.3.407-425.2002","article-title":"Human Telomerase and Its Regulation","volume":"66","author":"Cong","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.ceb.2006.03.003","article-title":"Telomerase regulation and stem cell behaviour","volume":"18","author":"Flores","year":"2006","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrm2848","article-title":"Telomeres: Protecting chromosomes against genome instability","volume":"11","author":"Karlseder","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/GCO.0000000000000061","article-title":"New genetic markers for male infertility","volume":"26","author":"Ferlin","year":"2014","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1093\/humrep\/det392","article-title":"In young men sperm telomere length is related to sperm number and parental age","volume":"28","author":"Ferlin","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1093\/humrep\/dev144","article-title":"Sperm telomere length is positively associated with the quality of early embryonic development","volume":"30","author":"Yang","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1093\/humrep\/dew061","article-title":"Sperm telomere length as a parameter of sperm quality in normozoospermic men","volume":"31","author":"Rocca","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.rbmo.2016.06.006","article-title":"Investigation of sperm telomere length as a potential marker of paternal genome integrity and semen quality","volume":"33","author":"Cariati","year":"2016","journal-title":"Reprod. Biomed. Online"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/REP-15-0375","article-title":"Spermatozoa telomeres determine telomere length in early embryos and offspring","volume":"151","author":"Rizos","year":"2016","journal-title":"Reproduction"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1126\/science.1147182","article-title":"Telomeric Repeat Containing RNA and RNA Surveillance Factors at Mammalian Chromosome Ends","volume":"318","author":"Azzalin","year":"2007","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.tcb.2014.08.007","article-title":"Telomere functions grounding on TERRA firma","volume":"25","author":"Azzalin","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_21","first-page":"103","article-title":"Telomeric Repeat-Containing RNA (TERRA) and Telomerase Are Components of Telomeres During Mammalian Gametogenesis1","volume":"90","author":"Vitelli","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.fertnstert.2014.06.005","article-title":"Telomere homeostasis is compromised in spermatocytes from patients with idiopathic infertility","volume":"102","author":"Capilla","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1093\/humrep\/14.5.1318","article-title":"The probability of abnormal preimplantation development can be predicted by a single static observation on pronuclear stage morphology","volume":"14","author":"Tesarik","year":"1999","journal-title":"Hum. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1093\/humrep\/17.7.1852","article-title":"Day 3 embryo transfer with combined evaluation at the pronuclear and cleavage stages compares favourably with day 5 blastocyst transfer","volume":"17","author":"Rienzi","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/30.10.e47","article-title":"Telomere measurement by quantitative PCR","volume":"30","author":"Cawthon","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ymeth.2016.08.004","article-title":"A practical qPCR approach to detect TERRA, the elusive telomeric repeat-containing RNA","volume":"114","author":"Feretzaki","year":"2017","journal-title":"Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4165","DOI":"10.1038\/emboj.2012.266","article-title":"A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection","volume":"31","author":"Deng","year":"2012","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4161\/nucl.2.2.15135","article-title":"Shelterin complex and associated factors at human telomeres","volume":"2","author":"Diotti","year":"2011","journal-title":"Nucl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/cr.2017.144","article-title":"Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex","volume":"27","author":"Hu","year":"2017","journal-title":"Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-genet-032918-021921","article-title":"Shelterin-Mediated Telomere Protection","volume":"52","year":"2018","journal-title":"Annu. Rev. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7181","DOI":"10.1007\/s11033-020-05551-y","article-title":"Telomere length: How the length makes a difference","volume":"47","author":"Lulkiewicz","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1146\/annurev-genet-102108-134841","article-title":"Telomeric Strategies: Means to an End","volume":"44","author":"Jain","year":"2010","journal-title":"Annu. Rev. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/sj.bjc.6603671","article-title":"Telomere and telomerase in stem cells","volume":"96","author":"Hiyama","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1007\/s10815-015-0574-3","article-title":"A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age","volume":"32","author":"Antunes","year":"2015","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_35","first-page":"305","article-title":"Telomere length: Lights and shadows on their role in human reproduction","volume":"100","author":"Rocca","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/ncb1685","article-title":"Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II","volume":"10","author":"Schoeftner","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"316","DOI":"10.7150\/ijbs.10528","article-title":"Role of TERRA in the Regulation of Telomere Length","volume":"11","author":"Wang","year":"2015","journal-title":"Int. J. Biol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cell.2017.06.017","article-title":"TERRA RNA Antagonizes ATRX and Protects Telomeres","volume":"170","author":"Chu","year":"2017","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1093\/embo-reports\/kvf055","article-title":"Requirement of functional telomeres for metaphase chromosome alignments and integrity of meiotic spindles","volume":"3","author":"Liu","year":"2002","journal-title":"EMBO Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/cen.13283","article-title":"Telomeric repeat-containing RNA (TERRA) related to polycystic ovary syndrome (PCOS)","volume":"86","author":"Wang","year":"2017","journal-title":"Clin. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0015-0282(02)03219-3","article-title":"Increased sperm nuclear DNA damage in normozoospermic infertile men: A prospective study","volume":"78","author":"Saleh","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.fertnstert.2006.05.060","article-title":"Evaluation of a transfer medium containing high concentration of hyaluronan in human in vitro fertilization","volume":"87","author":"Loutradi","year":"2007","journal-title":"Fertil. Steril."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1093\/oxfordjournals.humrep.a019263","article-title":"Sperm chromatin abnormalities can influence decondensation after intracytoplasmic sperm injection","volume":"11","author":"Sakkas","year":"1996","journal-title":"Hum. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S1642-431X(12)60027-8","article-title":"Role of oocyte quality in meiotic maturation and embryonic development","volume":"9","author":"Marteil","year":"2009","journal-title":"Reprod. Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:41:10Z","timestamp":1760161270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,25]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["genes12040475"],"URL":"https:\/\/doi.org\/10.3390\/genes12040475","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,25]]}}}