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
Abstract
1. Background
2. Methods
2.1. Data Collection
2.2. Inhibitory MicroRNA Prediction
2.3. Sequence Alignment between 5′UTR of Coronavirus and MicroRNA Seed Regions and Phylogenetic Trees
2.4. Literature-Mining Based Drug Repurposing
2.5. Multivariate Analysis
2.6. MIR-5004 Expression Analysis in Response to SARS-CoV-2 Infection: Meta-analysis Approach
2.7. Variant Discovery on Genomic Sequence of Hsa-MIR-5004-3p, 5′UTR Inhibitory MicroRNAs, as COVID-19 Risk Factors
3. Results
3.1. Comparative Analysis of the 5′UTR of Human Pathogenic and Non-Pathogenic Coronaviruses
3.2. Identifying the MicroRNAs that Can Bind to the Leader Sequence and TRS of SARS-CoV-2 (5′UTR Inhibitory MicroRNAs)
3.3. The Leader Sequence of SARS-CoV-2 Has a Unique Pattern of MicroRNA Binding, Compared with SARS, MERS, Bat, and Bovine Coronaviruses
3.4. Drug Repurposing to Induce 5′UTR Inhibitory MicroRNAs
3.5. Significant Decline in Expression of MIR-5004 after SARS-COV-2 Infection
3.6. hsa-miR-5004-3p Genomic Variation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Entities | Number | Relations | Number |
---|---|---|---|
Small molecules (including drugs) | 1,053,259 | Binding | 1,123,702 |
Protein | 138,106 | Biomarker | 120,448 |
Cell process | 9771 | Cell expression | 1,213,035 |
Cell Object | 607 | Chemical reaction | 58,888 |
Cells | 4155 | Clinical trial | 109,386 |
Clinical parameters | 5126 | Direct regulation | 766,707 |
Complex | 998 | Expression | 832,784 |
Diseases | 20,855 | Functional associations | 1,775,463 |
Functional class | 5489 | Genetic change | 379,261 |
Genetic Variant | 127,872 | Molsynthesis | 160,178 |
Organ | 3839 | Moltransport | 251,347 |
Treatments | 78 | Promoter binding | 44,619 |
Tissue | 574 | Protein modification | 73,859 |
Total number of entities | 1,370,729 | Quantitative change | 421,884 |
Regulation | 5,193,796 | ||
State change | 128,112 | ||
MicroRNA effects | 57,743 | ||
Total number of relations | 12,653,469 |
Experiment ID | Sample ID (NCBI) | Organism | Tissue/Cell Line | SARS-CoV-2 Infected/Non-Infected | Total Number of Reads | SARS-CoV-2 Strain |
---|---|---|---|---|---|---|
GSE150819 | SRR11811019 | Human | Lung bronchial organoids | Non-infected | 32,214,210 | Non-infected (mock) |
SRR11811020 | Human | Lung bronchial organoids | Non-infected | 32,443,162 | Non-infected (mock) | |
SRR11811021 | Human | Lung bronchial organoids | Non-infected | 33,310,500 | Non-infected (mock) | |
SRR11811022 | Human | Lung bronchial organoids | Infected | 31,662,278 | SARS-CoV-2/Hu/DP/Kng/19-020 | |
SRR11811023 | Human | Lung bronchial organoids | Infected | 35,953,491 | SARS-CoV-2/Hu/DP/Kng/19-020 | |
SRR11811024 | Human | Lung bronchial organoids | Infected | 32,416,198 | SARS-CoV-2/Hu/DP/Kng/19-020 | |
GSE147507 | SRR11517725-28 | Human | human lung biopsies | Non-infected | 57,660,692 | Non-infected (mock) |
SRR11517729-32 | Human | human lung biopsies | Non-infected | 40,524,836 | Non-infected (mock) | |
SRR11517733-36 | Human | human lung biopsies | Infected | 10,561,476 | USA-WA1/2020 | |
SRR11517737-40 | Human | human lung biopsies | Infected | 9,514,219 | USA-WA1/2020 | |
SRR11412215-18 | Human | Lung epithelium NHBE cells | Non-infected | 17,003,573 | Non-infected (mock) | |
SRR11412219-22 | Human | Lung epithelium NHBE cells | Non-infected | 16,311,121 | Non-infected (mock) | |
SRR11412223-26 | Human | Lung epithelium NHBE cells | Non-infected | 24,286,949 | Non-infected (mock) | |
SRR11412227-30 | Human | Lung epithelium NHBE cells | Infected | 15,032,096 | USA-WA1/2020 | |
SRR11412231-34 | Human | Lung epithelium NHBE cells | Infected | 15,108,090 | USA-WA1/2020 | |
SRR11412235-38 | Human | Lung epithelium NHBE cells | Infected | 44,210,735 | USA-WA1/2020 | |
SRR11412239-42 | Human | Lung alveolar A549 cells | Non-infected | 27,013,945 | Non-infected (mock) | |
SRR11412243-46 | Human | Lung alveolar A549 cells | Non-infected | 14,744,844 | Non-infected (mock) | |
SRR11412247-50 | Human | Lung alveolar A549 cells | Non-infected | 11,683,707 | Non-infected (mock) | |
SRR11412251-54 | Human | Lung alveolar A549 cells | Infected | 34,141,057 | USA-WA1/2020 | |
SRR11412255-59 | Human | Lung alveolar A549 cells | Infected | 29,681,064 | USA-WA1/2020 | |
SRR11412260-63 | Human | Lung alveolar A549 cells | Infected | 20,603,153 | USA-WA1/2020 | |
SRR11517744 | Human | Lung-derived Calu-3 cells | Non-infected | 9,324,151 | Non-infected (mock) | |
SRR11517745 | Human | Lung-derived Calu-3 cells | Non-infected | 17,436,078 | Non-infected (mock) | |
SRR11517746 | Human | Lung-derived Calu-3 cells | Non-infected | 37,787,485 | Non-infected (mock) | |
SRR11517747 | Human | Lung-derived Calu-3 cells | Infected | 23,623,325 | USA-WA1/2020 | |
SRR11517748 | Human | Lung-derived Calu-3 cells | Infected | 13,583,713 | USA-WA1/2020 | |
SRR11517749 | Human | Lung-derived Calu-3 cells | Infected | 28,688,015 | USA-WA1/2020 | |
SRR11517699 | Ferret | Trachea | Non-infected | 328,105,259 | Non-infected (mock) | |
SRR11517700 | Ferret | Trachea | Non-infected | 5,210,254 | Non-infected (mock) | |
SRR11517701 | Ferret | Trachea | Non-infected | 4,746,327 | Non-infected (mock) | |
SRR11517702 | Ferret | Trachea | Non-infected | 5,163,699 | Non-infected (mock) | |
SRR11517703 | Ferret | Trachea | Infected | 9,169,859 | USA-WA1/2020 | |
SRR11517707 | Ferret | Trachea | Infected | 14,124,547 | USA-WA1/2020 | |
SRR11517711 | Ferret | Trachea | Infected | 12,933,325 | USA-WA1/2020 | |
SRR11517715 | Ferret | Trachea | Infected | 14,644,347 | USA-WA1/2020 | |
GSE159522 | SRR12828440-43 | Human | Lung alveolar A549 cells | Non-infected | 19,152,790 | Non-infected (mock) |
SRR12828444-47 | Human | Lung alveolar A549 cells | Non-infected | 19,381,530 | Non-infected (mock) | |
SRR12828448-51 | Human | Lung alveolar A549 cells | Non-infected | 16,483,541 | USA-WA1/2020 | |
SRR12828428-31 | Human | Lung alveolar A549 cells | Infected | 17,644,925 | USA-WA1/2020 | |
SRR12828432-35 | Human | Lung alveolar A549 cells | Infected | 19,504,193 | USA-WA1/2020 | |
SRR12828436-39 | Human | Lung alveolar A549 cells | Infected | 19,491,861 | USA-WA1/2020 |
MicroRNA | Organism | Thermodynamic Binding Energy against Leader Sequence (kcal/mol) | ||||
---|---|---|---|---|---|---|
SARS-COV-2 | SARS | MERS | Bat Coronavirus | Bovine Coronavirus | ||
ptc-miR474b | Populus trichocarpa | −27.3 | −24.5 | −21.6 | −21.5 | −17 |
ptc-miR474a | Populus trichocarpa | −27.3 | −22.2 | −22.8 | −22.2 | −18.1 |
csa-let-7d | Ciona savignyi | −25.1 | −22.7 | −24.6 | −24.6 | −19 |
cin-let-7d-5p | Ciona intestinalis | −25.1 | −22.7 | −24.6 | −24.6 | −19 |
gga-miR-6608-3p | Gallus gallus | −25 | −23.6 | −30.1 | −14.6 | −17.1 |
eca-miR-9080 | Equus caballus | −23.4 | −27.7 | −15.9 | −15.9 | −16.5 |
csi-miR3953 | Citrus sinensis | −22.5 | −22.4 | −27.2 | −14.1 | −16.8 |
ame-miR-3741 | Apis mellifera | −21.9 | −20.9 | −35.2 | −16 | −21.7 |
cel-miR-8207-3p | Caenorhabditis elegans | −20.5 | −22 | −25.6 | −12.2 | −22.6 |
ppy-miR-1273a | Pongo pygmaeus | −20.1 | −21.1 | −23.4 | −18.7 | −19.5 |
hsa-miR-5004-3p | Homo sapiens | −19.4 | −25.9 | −17.7 | −17.7 | −14.1 |
bta-miR-2284ab | Bos taurus | −19.3 | −21.6 | −16.8 | −19.9 | −13.8 |
oan-miR-1395-5p | Ornithorhynchus anatinus | −19.3 | −27.8 | −17.5 | −15.3 | −13.4 |
mdo-miR-137b-5p | Monodelphis domestica | −17.7 | −26.8 | −19.4 | −15.1 | −16.8 |
dme-miR-4949-3p | Drosophila melanogaster | −17.7 | −17.4 | −13.2 | −12.6 | −24.4 |
ssc-miR-9833-5p | Sus scrofa | −17.1 | −16.3 | −15.9 | −15.9 | −15.7 |
ptc-miR6464 | Populus trichocarpa | −16.2 | −15.4 | −13.7 | −13.7 | −13.1 |
mtr-miR2629g | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629f | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629e | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629d | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629c | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629b | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
mtr-miR2629a | Medicago truncatula | −15.1 | −21.7 | −13.1 | −13.1 | −14.1 |
bmo-miR-3293 | Bombyx mori | −13.9 | −14.8 | −15.7 | −12.7 | −16 |
dsi-miR-986-3p | Drosophila simulans | −12.4 | −16.5 | −25.1 | −25.1 | −19.7 |
dme-miR-986-3p | Drosophila melanogaster | −12.4 | −16.5 | −25.1 | −25.1 | −19.7 |
dsi-miR-986-3p | Drosophila simulans | −12.4 | −16.5 | −25.1 | −25.1 | −19.7 |
dme-miR-986-3p | Drosophila melanogaster | −12.4 | −16.5 | −25.1 | −25.1 | −19.7 |
mmu-miR-6957-3p | Mus musculus | −11.6 | −13.5 | −12.2 | −12.2 | −12.1 |
ppc-miR-83-5p | Pristionchus pacificus | −11.4 | −14.7 | −10.9 | −11.4 | −17.6 |
cme-miR1863 | Cucumis melo | −11.3 | −10.5 | −12.5 | −12.5 | −15.2 |
cel-miR-2211-5p | Caenorhabditis elegans | −10.7 | −10.6 | −10.5 | −10.3 | −12.2 |
ath-miR5638a | Arabidopsis thaliana | −9.8 | −7.8 | −10.9 | −10.9 | −16.6 |
bdi-miR5065 | Brachypodium distachyon | −9.7 | −11.8 | −23.6 | −23.6 | −16.9 |
bdi-miR5065 | Brachypodium distachyon | −9.7 | −11.8 | −23.6 | −23.6 | −16.9 |
oan-miR-1421l-2-3p | Ornithorhynchus anatinus | −9.7 | −10.8 | −12.6 | −11.1 | −21.2 |
mghv-miR-M1-2-3p | Mouse gammaherpesvirus 68 | −9.4 | −8.8 | −8.3 | −5.7 | −7.5 |
dps-miR-2535-3p | Drosophila pseudoobscura | −9.3 | −10.6 | −17.1 | −17.1 | −19.6 |
Average | −16.33 | −18.58 | −18.34 | −16.35 | −16.61 |
rsId | Chr. | Location | Ref | Alt. | MicroRNA | Gene Region | Translational Impact | GERP++ Score |
---|---|---|---|---|---|---|---|---|
rs369274154 | 6 | 33406128 | T | C | MIR5004 | 5UTR | ||
rs371304188 | 6 | 33406147 | C | T | MIR5004 | 5UTR | ||
rs375913209 | 6 | 33406168 | C | T | MIR5004 | 5UTR | ||
Not assigned | 6 | 33406194 | A | C | MIR5004 | 5UTR | splice-disrupt | 4.77 |
Not assigned | 6 | 33406194 | A | G | MIR5004 | 5UTR | splice-disrupt | 4.77 |
Not assigned | 6 | 33406194 | A | T | MIR5004 | 5UTR | splice-disrupt | 4.77 |
Not assigned | 6 | 33406195 | G | A | MIR5004 | 5UTR | splice-disrupt | 4.77 |
Not assigned | 6 | 33406195 | G | C | MIR5004 | 5UTR | splice-disrupt | 4.77 |
Not assigned | 6 | 33406195 | G | T | MIR5004 | 5UTR | splice-disrupt | 4.77 |
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Mohammadi-Dehcheshmeh, M.; Moghbeli, S.M.; Rahimirad, S.; Alanazi, I.O.; Shehri, Z.S.A.; Ebrahimie, E. 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. Cells 2021, 10, 319. https://doi.org/10.3390/cells10020319
Mohammadi-Dehcheshmeh M, Moghbeli SM, Rahimirad S, Alanazi IO, Shehri ZSA, Ebrahimie E. 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. Cells. 2021; 10(2):319. https://doi.org/10.3390/cells10020319
Chicago/Turabian StyleMohammadi-Dehcheshmeh, Manijeh, Sadrollah Molaei Moghbeli, Samira Rahimirad, Ibrahim O. Alanazi, Zafer Saad Al Shehri, and Esmaeil Ebrahimie. 2021. "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" Cells 10, no. 2: 319. https://doi.org/10.3390/cells10020319
APA StyleMohammadi-Dehcheshmeh, M., Moghbeli, S. M., Rahimirad, S., Alanazi, I. O., Shehri, Z. S. A., & Ebrahimie, E. (2021). 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. Cells, 10(2), 319. https://doi.org/10.3390/cells10020319