A Transcription Regulatory Sequence in the 5' Untranslated Region of SARS-CoV-2 Is Vital for Virus Replication with an Altered Evolutionary Pattern against Human Inhibitory MicroRNAs
journal contributionposted on 31.03.2021, 06:35 by Manijeh Mohammadi Dehcheshmeh, SM Moghbeli, S Rahimirad, IO Alanazi, ZSA Shehri, Esmaeil Ebrahimie
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' 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 < 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.
We would like to greatly thank Genomics Research Platform, College of Science, Health and Engineering of La Trobe University as well as School of Animal and Veterinary Sciences of The University of Adelaide for providing the computational resources to perform this study. This research was supported by use of the Nectar Research Cloud, a collaborative Australian research platform supported by the National Collaborative Research Infrastructure Strategy (NCRIS). Additionally, this work was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. We thank Jeremy Timmis, Emeritus Professor of Genetics at The University of Adelaide, for editing of the revised manuscript.
Article NumberARTN 319
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Science & TechnologyLife Sciences & BiomedicineCell BiologyCOVID-19biomarkerdrug repurposingmicroRNASARS-CoV-2 replicationmicroRNA vaccinenanoparticle vaccinevariant discoveryAnimalsHumansMicroRNAs5' Untranslated RegionsRNA, PlantComputational BiologyEvolution, MolecularVirus ReplicationNucleic Acid ConformationGenome, ViralSARS-CoV-2