{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:06:12Z","timestamp":1790687172785,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Our knowledge of the evolution and the role of untranslated region (UTR) in SARS-CoV-2 pathogenicity is very limited. Leader sequence, originated from UTR, is found at the 5\u2032 ends of all encoded SARS-CoV-2 transcripts, highlighting its importance. Here, evolution of leader sequence was compared between human pathogenic and non-pathogenic coronaviruses. Then, profiling of microRNAs that can inactivate the key UTR regions of coronaviruses was carried out. A distinguished pattern of evolution in leader sequence of SARS-CoV-2 was found. Mining all available microRNA families against leader sequences of coronaviruses resulted in discovery of 39 microRNAs with a stable thermodynamic binding energy. Notably, SARS-CoV-2 had a lower binding stability against microRNAs. hsa-MIR-5004-3p was the only human microRNA able to target the leader sequence of SARS and to a lesser extent, also SARS-CoV-2. However, its binding stability decreased remarkably in SARS-COV-2. We found some plant microRNAs with low and stable binding energy against SARS-COV-2. Meta-analysis documented a significant (p &lt; 0.01) decline in the expression of MIR-5004-3p after SARS-COV-2 infection in trachea, lung biopsy, and bronchial organoids as well as lung-derived Calu-3 and A549 cells. The paucity of the innate human inhibitory microRNAs to bind to leader sequence of SARS-CoV-2 can contribute to its high replication in infected human cells.<\/jats:p>","DOI":"10.3390\/cells10020319","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T12:02:10Z","timestamp":1612440130000},"page":"319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["A Transcription Regulatory Sequence in the 5\u2032 Untranslated Region of SARS-CoV-2 Is Vital for Virus Replication with an Altered Evolutionary Pattern against Human Inhibitory MicroRNAs"],"prefix":"10.3390","volume":"10","author":[{"given":"Manijeh","family":"Mohammadi-Dehcheshmeh","sequence":"first","affiliation":[{"name":"La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne, VIC 3086, Australia"},{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA 5371, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadrollah Molaei","family":"Moghbeli","sequence":"additional","affiliation":[{"name":"Department of Animal Science, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI 1675, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1997-7327","authenticated-orcid":false,"given":"Samira","family":"Rahimirad","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 1497716316, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8479-7875","authenticated-orcid":false,"given":"Ibrahim O.","family":"Alanazi","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh 6086, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zafer Saad Al","family":"Shehri","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, KSA, Al dawadmi 1678, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4431-2861","authenticated-orcid":false,"given":"Esmaeil","family":"Ebrahimie","sequence":"additional","affiliation":[{"name":"La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne, VIC 3086, Australia"},{"name":"School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA 5371, Australia"},{"name":"School of BioSciences, The University of Melbourne, Melbourne, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.virusres.2015.02.025","article-title":"The structure and functions of coronavirus genomic 3\u2032 and 5\u2032 ends","volume":"206","author":"Yang","year":"2015","journal-title":"Virus Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1146\/annurev-virology-100114-055218","article-title":"Continuous and discontinuous RNA synthesis in coronaviruses","volume":"2","author":"Sola","year":"2015","journal-title":"Annu. 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