Preview

Proceedings of the National Academy of Sciences of Belarus, Biological Series

Advanced search

Effect of retained introns on the coding potential of RNA molecules in human leukemia cells

https://doi.org/10.29235/1029-8940-2025-70-2-146-160

Abstract

Intron retention is a mode of alternative splicing in which at least one intron is retained in mature RNA molecules. The inclusion of an intron sequence within the coding region of the mRNA can change the structure, properties and, in some cases, the functions of the corresponding protein. Furthermore, some of these altered proteins can be immunogenic and are considered as potential targets for the treatment of a number of diseases. In general, however, the effect of intron retention on the coding potential of RNA molecules remains poorly studied.

This paper presents the results of a combined transcriptomic-proteomic study of 3540 intron sequences retained in mature RNA molecules of genes that are active in human leukemia cells. The introns were classified according to their coding potential and seven possible ways in which intron retention can influence the subsequent translation of the corresponding transcripts were described. A total of 56 translation-capable intronic sequences were identified, and 3 of them produce previously unknown polypeptides.

About the Authors

K. V. Huzava
Belarusian State University
Belarus

Katsiaryna V. Huzava – Postgraduate Student, Junior Researcher

4, Nezavisimosti Ave., 220030, Minsk



A. A. Gavrichkov
Belarusian State University
Belarus

Aleksey A. Gavrichkov – Student

4, Nezavisimosti Ave., 220030, Minsk



I. M. Ilyushonak
Belarusian State University
Belarus

Ilya M. Ilyushonak – Ph. D. (Biol.), Associate Professor

4, Nezavisimosti Ave., 220030, Minsk



T. A. Ramanouskaya
Belarusian State University
Belarus

Tatsiana V. Ramanouskaya – Ph. D. (Biol.), Associate Professor

4, Nezavisimosti Ave., 220030, Minsk



M. A. Likhavets
Belarusian State University
Belarus

Maksim A. Likhavets – Master Student

4, Nezavisimosti Ave., 220030, Minsk



V. V. Skakun
Belarusian State University
Belarus

Victor V. Skakun – Ph. D. (Math.), Associate Professor

4, Nezavisimosti Ave., 220030, Minsk



M. M. Yatskou
Belarusian State University
Belarus

Mikalai M. Yatskou – Ph. D. (Math.), Associate Professor, Head of the Department

4, Nezavisimosti Ave., 220030, Minsk



V. V. Grinev
Belarusian State University
Belarus

Vasily V. Grinev – Ph. D. (Biol.), Associate Professor

4, Nezavisimosti Ave., 220030, Minsk



References

1. The status of the human gene catalogue / P. Amaral, S. Carbonell-Sala, F. M. De La Vega [et al.] // Nature. – 2023. – Vol. 622, N 7981. – P. 41–47. https://doi.org/10.1038/s41586-023-06490-x

2. Ramanouskaya, T. V. The determinants of alternative RNA splicing in human cells / T. V. Ramanouskaya, V. V. Grinev // Molecular Genetics and Genomics. – 2017. – Vol. 292, N 6. – P. 1175–1195. https://doi.org/10.1007/s00438-017-1350-0

3. Liu, Q. Alternative splicing and isoforms: from mechanisms to diseases / Q. Liu, L. Fang, C. Wu // Genes. – 2022. – Vol. 13, N 3. – Art. 401. https://doi.org/10.3390/genes13030401

4. Intron retention as a mode for RNA-Seq data analysis / J.-T. Zheng, C.-X. Lin, Z.-Y. Fang, H.-D. Li // Frontiers in Genetics. – 2020. – Vol. 11. – Art. 586. https://doi.org/10.3389/fgene.2020.00586

5. Decoding of exon splicing patterns in the human RUNX1–RUNX1T1 fusion gene / V. V. Grinev, A. A. Migas, A. D. Kirsanava [et al.] // The International Journal of Biochemistry and Cell Biology. – 2015. – Vol. 68. – P. 48–58. https://doi.org/10.1016/j.biocel.2015.08.017

6. Differential fates of introns in gene expression due to global alternative splicing / A. Kumari, S. Sedehizadeh, J. D. Brook [et al.] // Human Genetics. – 2021. – Vol. 141. – P. 31–47. https://doi.org/10.1007/s00439-021-02409-6

7. Holding on to junk bonds: intron retention in cancer and therapy / G. Monteuuis, U. Schmitz, V. Petrova [et al.] // Cancer Research. – 2021. – Vol. 81, N 4. – P. 779–789. https://doi.org/10.1158/0008-5472.can-20-1943

8. RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia / V. V. Grinev, F. Barneh, I. M. Ilyushonak [et al.] // Nature Communications. – 2021. – Vol. 12. – Art. 520. https://doi.org/10.1038/s41467-02020848-z

9. The European Nucleotide Archive in 2022 / J. Burgin, A. Ahamed, C. Cummins [et al.] // Nucleic Acids Research. – 2023. – Vol. 51, N D1. – P. D121–D125. https://doi.org/10.1093/nar/gkac1051

10. Grinev V. V. Intron retention in the transcriptome of leukemic and normal human blood cells. Molekulyarnaya i pri kladnaya genetika [Molecular and Applied Genetics], 2018, vol. 25, pp. 45–56 (in Russian).

11. Biostrings: Efficient manipulation of biological strings. – URL: https://bioconductor.org/packages/Biostrings (date of access: 12.09.2024).

12. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads / M. Pertea, G. M. Pertea, C. M. Anto- nescu [et al.] // Nature Biotechnology. – 2015. – Vol. 33. – P. 290–295. https://doi.org/10.1038/nbt.3122

13. Liao, Y. The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads / Y. Liao, G. K. Smyth, W. Shi // Nucleic Acids Research. – 2019. – Vol. 47, N 8. – P. e47. https://doi.org/10.1093/nar/gkz114

14. GitHub. – URL: https://github.com/VGrinev/TranscriptomicFeatures (date of access: 12.09.2024).

15. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput / V. Demichev, Ch. B. Messner, S. I. Vernardis [et al.] // Nature Methods. – 2020. – Vol. 17. – P. 41–44. https://doi.org/10.1038/s41592-019-0638-x

16. UniProt: the universal protein knowledgebase in 2023 / The UniProt Consortium // Nucleic Acids Research. – 2023. – Vol. 51, N D1 – P. D523–D531. https://doi.org/10.1093/nar/gkac1052

17. Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation / Sh. Pujar, N. A. O’Leary, C. M. Farrell [et al.] // Nucleic Acids Research. – 2018. – Vol. 46, iss. D1. – P. D221–D228. https://doi.org/10.1093/nar/gkx1031

18. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation / N. A. O’Leary, M. W. Wright, J. R. Brister [et al.] // Nucleic Acids Research. – 2016. – Vol. 44, N D1. – P. D733–D745. https://doi.org/10.1093/nar/gkv1189

19. The comprehensive R archive network. – URL: https://cran.r-project.org/ (date of access: 12.09.2024).

20. Bioconductor: Open source software for Bioinformatics. – URL: https://www.bioconductor.org/ (date of access: 12.09.2024).

21. The Need for Guidelines in Publication of Peptide and Protein Identification Data / S. Carr, R. Aebersold, M. Baldwin [et al.] // Molecular & Cellular Proteomics. – 2004. – Vol. 3, N 6. – P. 531–533. https://doi.org/10.1074/mcp.t400006-mcp200

22. A Practical Guide to Small Protein Discovery and Characterization Using Mass Spectrometry / Ch. H. Ahrens, J. T. Wade, M. M. Champion, J. D. Langer // Journal of Bacteriology. – 2022. – Vol. 204, N 1. – Art. 00353. https://doi.org/10.1128/jb.00353-21

23. The Gene Ontology knowledgebase in 2023 / The Gene Ontology Consortium, S. A. Aleksander, J. Balhoff [et al.] // Genetics. – 2023. – Vol. 224, N 11. – Art. 31. https://doi.org/10.1093/genetics/iyad031

24. BLAST. – URL: https://blast.ncbi.nlm.nih.gov/Blast.cgi (date of access: 12.09.2024).

25. Protein neddylation and its role in health and diseases / Sh. Zhang, Q. Yu, Zh. Li [et al.] // Signal Transduction and Targeted Therapy. – 2024. – Vol. 9. – Art. 85. https://doi.org/10.1038/s41392-024-01800-9

26. OGT as potential novel target: Structure, function and inhibitors / N. Zhang, H. Jiang, K. Zhang [et al.] // Chemico-Biological Interactions. – Vol. 357. – Art. 109886. https://doi.org/10.1016/j.cbi.2022.109886

27. Claro da Silva T. The solute carrier family 10 (SLC10): Beyond bile acid transport / T. Claro da Silva, J. E. Polli, P. W. Swaan // Molecular Aspects of Medicine. – 2013. – Vol. 34, N 2–3. – P. 252–269. https://doi.org/10.1016/j.mam.2012.07.004

28. ORFhunteR: An accurate approach to the automatic identification and annotation of open reading frames in human mRNA molecules / V. V. Grinev, M. M. Yatskou, V. V. Skakun [et al.] // Software Impacts. – 2022. – Vol. 12. – Art. 100268. https://doi.org/10.1016/j.simpa.2022.100268

29. Open Reading Frame Finder. – URL: https://www.ncbi.nlm.nih.gov/orffinder/ (date of access: 12.09.2024).

30. A high-resolution map of human RNA translation / S. P. Chothani, E. Adami, A. A. Widjaja [et al.] // Molecular Cell. – 2022. – Vol. 82, N 15. – P. 2885–2899. https://doi.org/10.1016/j.molcel.2022.06.023

31. The conserved domain database in 2023 / J. Wang, F. Chitsaz, M. K. Derbyshire [et al.] // Nucleic Acids Research. – 2023. – Vol. 51, N D1. – P. D384–D388. https://doi.org/10.1093/nar/gkac1096

32. InterPro in 2022 / T. Paysan-Lafosse, M. Blum, S. Chuguransky [et al.] // Nucleic Acids Research. – 2023. – Vol. 51, N D1. – P. D418–D427. https://doi.org/10.1093/nar/gkac993

33. The wide and growing range of lamin B-related diseases: from laminopathies to cancer / C. Evangelisti, I. Rusciano, S. Mongiorgi [et al.] // Cellular and Molecular Life Sciences. – 2022. – Vol. 79. – Art. 126. https://doi.org/10.1007/s00018-021-04084-2

34. Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction / R. Anzai, M. Tsuji, S. Yamashita [et al.] // Brain and Development. – 2021. – Vol. 43, N 3. – P. 402–410. https://doi.org/10.1016/j.braindev.2020.10.013

35. Function of BCLAF1 in human disease (Review) / Z. Yu, J. Zhu, H. Wang [et al.] // Oncology Letters. – 2022. – Vol. 23, N 2. – Art. 58. https://doi.org/10.3892/ol.2021.13176

36. Heterogeneous nuclear ribonucleoprotein (hnRNPL) in cancer / J. Gu, Zh. Chen, X. Chen, Zh. Wang // Clinica Chimica Acta. – 2020. – Vol. 507. – P. 286–294. https://doi.org/10.1016/j.cca.2020.04.040

37. Human NF-κB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance / M. Coccia, A. Rossi, A. Riccio [et al.] // Proceedings of the National Academy of Sciences. – 2017. – Vol. 114, N 5. – P. 1045–1050. https://doi.org/10.1073/pnas.1616112114

38. SH3BP1, an Exocyst-Associated RhoGAP, Inactivates Rac1 at the Front to Drive Cell Motility / M. C. Parrini, A. Sadou- Dubourgnoux, K. Aoki [et al.] // Molecular Cell. – 2011. – Vol. 42, N 5. – P. 650–661. https://doi.org/10.1016/j.molcel.2011.03.032

39. The role and function of Ras-association domain family in cancer: A review / M. R. Zinatizadeh, S. A. Momeni, P. K. Zarandi [et al.] // Genes and Diseases. – 2019. – Vol. 6, N 4. – P. 378–384. https://doi.org/10.1016/j.gendis.2019.07.008

40. The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleo- tide transporters / M. A. Di Noia, S. Todisco, A. Cirigliano [et al.] // Journal of Bio logical Chemistry. – 2014. – Vol. 289, N 48. – P. 33137–33148. https://doi.org/10.1074/jbc.m114.610808


Review

Views: 110


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1029-8940 (Print)
ISSN 2524-230X (Online)