The evidence discussed in Chapters 1–3 indicates that in living organisms at least the primary control of gene expression lies at the level of transcription. However, in eukaryotes, several cases exist where changes in the rate of synthesis of a particular protein occur without a change in the transcription rate of the corresponding gene or where post-transcriptional controls operate as a significant supplement to transcriptional control. This indicates that in these cases regulatory processes are operating at the level of one or more of the post-transcriptional events, as described in Chapter 8. Indeed, in some lower organisms, post-transcriptional regulation may constitute the predominant form of regulation of gene expression.
Multiple-choice questions
Questions for Discussion
- Alternative splicing plays a key role in sex determination in invertebrates such as Drosophila. This leads to the question of whether splicing-controlled sex determination is exclusive to invertebrates or if it can be found in vertebrates. Your answer should be supported with specific examples.
- Discuss the significance of alternative splicing in the evolution of multicellular organisms. If alternative splicing is critical for eukaryotic cells, how do you explain its existence in several viruses.
- Polyadenylation is a crucial characteristic of eukaryotic mRNA, necessary for regulating mRNA function and stability. However, certain eukaryotic mRNAs, such as histone mRNA, lack poly(A). Discuss how poly(A)-less mRNA regulates their stability and other molecular processes.
- Discuss the role of RNA editing and modifications in RNA stability and gene expression.
- Discuss how viruses regulate its own and host non-coding RNAs to control the epigenome to bolster their survival.
Further Reading
9.1 Alternative RNA splicing
Blake, D., & Lynch, K. W. (2021). The three as: Alternative splicing, alternative polyadenylation and their impact on apoptosis in immune function. Immunological Reviews, 304(1), 30–50. https://doi.org/10.1111/imr.13018
Cherry, S., & Lynch, K. W. (2020). Alternative splicing and cancer: Insights, opportunities, and challenges from an expanding view of the transcriptome. Genes & Development, 34(15–16), 1005–1016. https://doi.org/10.1101/gad.338962.120
Gehring, N. H., & Roignant, J.-Y. (2021). Anything but Ordinary—Emerging Splicing Mechanisms in Eukaryotic Gene Regulation. Trends in Genetics: TIG, 37(4), 355–372. https://doi.org/10.1016/j.tig.2020.10.008
Marasco, L. E., & Kornblihtt, A. R. (2023). The physiology of alternative splicing. Nature Reviews. Molecular Cell Biology, 24(4), 242–254. https://doi.org/10.1038/s41580-022-00545-z
Marcelo, A., Koppenol, R., de Almeida, L. P., Matos, C. A., & Nóbrega, C. (2021). Stress granules, RNA-binding proteins and polyglutamine diseases: Too much aggregation? Cell Death & Disease, 12(6), 592. https://doi.org/10.1038/s41419-021-03873-8
Petasny, M., Bentata, M., Pawellek, A., Baker, M., Kay, G., & Salton, M. (2021). Splicing to Keep Cycling: The Importance of Pre-mRNA Splicing during the Cell Cycle. Trends in Genetics: TIG, 37(3), 266–278. https://doi.org/10.1016/j.tig.2020.08.013
Zhang, J., Zhang, Y.-Z., Jiang, J., & Duan, C.-G. (2020). The Crosstalk Between Epigenetic Mechanisms and Alternative RNA Processing Regulation. Frontiers in Genetics, 11, 998. https://doi.org/10.3389/fgene.2020.00998
Änkö M.L. & Neugebauer K.M. (2012) RNA–protein interactions in vivo: global gets specific. Trends Biochem Sci 37:255–262.
Nilsen T.W. & Graveley B.R. (2010) Expansion of the eukaryotic proteome by alternative RNA splicing. Nature 463:457–463.
9.2 Regulation of polyadenylation
Arora, A., Goering, R., Lo, H. Y. G., Lo, J., Moffatt, C., & Taliaferro, J. M. (2021). The Role of Alternative Polyadenylation in the Regulation of Subcellular RNA Localization. Frontiers in Genetics, 12, 818668. https://doi.org/10.3389/fgene.2021.818668
Gallicchio, L., Olivares, G. H., Berry, C. W., & Fuller, M. T. (2023). Regulation and function of alternative polyadenylation in development and differentiation. RNA Biology, 20(1), 908–925. https://doi.org/10.1080/15476286.2023.2275109
Mitschka, S., & Mayr, C. (2022). Context-specific regulation and function of mRNA alternative polyadenylation. Nature Reviews. Molecular Cell Biology, 23(12), 779–796. https://doi.org/10.1038/s41580-022-00507-5
Passmore, L. A., & Coller, J. (2022). Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Nature Reviews. Molecular Cell Biology, 23(2), 93–106. https://doi.org/10.1038/s41580-021-00417-y
Ruta, V., Pagliarini, V., & Sette, C. (2021). Coordination of RNA Processing Regulation by Signal Transduction Pathways. Biomolecules, 11(10), 1475. https://doi.org/10.3390/biom11101475
Smith, R. W. P., & Gray, N. K. (2010). Poly(A)-binding protein (PABP): A common viral target. The Biochemical Journal, 426(1), 1–12. https://doi.org/10.1042/BJ20091571
9.3 RNA editing
Eisenberg, E. (2021). Proteome Diversification by RNA Editing. Methods in Molecular Biology (Clifton, N.J.), 2181, 229–251. https://doi.org/10.1007/978-1-0716-0787-9_14
Lukeš, J., Kaur, B., & Speijer, D. (2021). RNA Editing in Mitochondria and Plastids: Weird and Widespread. Trends in Genetics: TIG, 37(2), 99–102. https://doi.org/10.1016/j.tig.2020.10.004
Pfeiffer, L. S., & Stafforst, T. (2023). Precision RNA base editing with engineered and endogenous effectors. Nature Biotechnology, 41(11), 1526–1542. https://doi.org/10.1038/s41587-023-01927-0
9.4 Regulation of RNA transport
De Magistris, P. (2021). The Great Escape: mRNA Export through the Nuclear Pore Complex. International Journal of Molecular Sciences, 22(21), 11767. https://doi.org/10.3390/ijms222111767
Palazzo, A. F., Qiu, Y., & Kang, Y. M. (2024). mRNA nuclear export: How mRNA identity features distinguish functional RNAs from junk transcripts. RNA Biology, 21(1), 1–12. https://doi.org/10.1080/15476286.2023.2293339
Wende, W., Friedhoff, P., & Sträßer, K. (2019). Mechanism and Regulation of Co-transcriptional mRNP Assembly and Nuclear mRNA Export. Advances in Experimental Medicine and Biology, 1203, 1–31. https://doi.org/10.1007/978-3-030-31434-7_1
Xie, Y., & Ren, Y. (2019). Mechanisms of nuclear mRNA export: A structural perspective. Traffic (Copenhagen, Denmark), 20(11), 829–840. https://doi.org/10.1111/tra.12691
9.5 Regulation of RNA stability
Frederick, M. I., & Heinemann, I. U. (2021). Regulation of RNA stability at the 3’ end. Biological Chemistry, 402(4), 425–431. https://doi.org/10.1515/hsz-2020-0325
Iwakawa, H.-O., & Tomari, Y. (2022). Life of RISC: Formation, action, and degradation of RNA-induced silencing complex. Molecular Cell, 82(1), 30–43. https://doi.org/10.1016/j.molcel.2021.11.026
Mattay, J. (2022). Noncanonical metabolite RNA caps: Classification, quantification, (de)capping, and function. Wiley Interdisciplinary Reviews. RNA, 13(6), e1730. https://doi.org/10.1002/wrna.1730
Murakami, S., & Jaffrey, S. R. (2022). Hidden codes in mRNA: Control of gene expression by m6A. Molecular Cell, 82(12), 2236–2251. https://doi.org/10.1016/j.molcel.2022.05.029
Niehrs, C., & Luke, B. (2020). Regulatory R-loops as facilitators of gene expression and genome stability. Nature Reviews. Molecular Cell Biology, 21(3), 167–178. https://doi.org/10.1038/s41580-019-0206-3
9.6 Regulation of translation
Boye, E., & Grallert, B. (2020). eIF2α phosphorylation and the regulation of translation. Current Genetics, 66(2), 293–297. https://doi.org/10.1007/s00294-019-01026-1
Daverkausen-Fischer, L., Draga, M., & Pröls, F. (2022). Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum. International Journal of Molecular Sciences, 23(10), 5576. https://doi.org/10.3390/ijms23105576
Farache, D., Antine, S. P., & Lee, A. S. Y. (2022). Moonlighting translation factors: Multifunctionality drives diverse gene regulation. Trends in Cell Biology, 32(9), 762–772. https://doi.org/10.1016/j.tcb.2022.03.006
Ishikawa, K. (2021). Multilayered regulation of proteome stoichiometry. Current Genetics, 67(6), 883–890. https://doi.org/10.1007/s00294-021-01205-z
Ruiz-Orera, J., & Albà, M. M. (2019). Translation of Small Open Reading Frames: Roles in Regulation and Evolutionary Innovation. Trends in Genetics: TIG, 35(3), 186–198. https://doi.org/10.1016/j.tig.2018.12.0037.7
9.7 Post-transcriptional inhibition of gene expression by small RNAs
Bédard, A.-S. V., Hien, E. D. M., & Lafontaine, D. A. (2020). Riboswitch regulation mechanisms: RNA, metabolites and regulatory proteins. Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, 1863(3), 194501. https://doi.org/10.1016/j.bbagrm.2020.194501
Carvalho Barbosa, C., Calhoun, S. H., & Wieden, H.-J. (2020). Non-coding RNAs: What are we missing? Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire, 98(1), 23–30. https://doi.org/10.1139/bcb-2019-0037
Correia de Sousa, M., Gjorgjieva, M., Dolicka, D., Sobolewski, C., & Foti, M. (2019). Deciphering miRNAs’ Action through miRNA Editing. International Journal of Molecular Sciences, 20(24), 6249. https://doi.org/10.3390/ijms20246249
Pagliarani, C., & Gambino, G. (2019). Small RNA Mobility: Spread of RNA Silencing Effectors and its Effect on Developmental Processes and Stress Adaptation in Plants. International Journal of Molecular Sciences, 20(17), 4306. https://doi.org/10.3390/ijms20174306
Saliminejad, K., Khorram Khorshid, H. R., Soleymani Fard, S., & Ghaffari, S. H. (2019). An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. Journal of Cellular Physiology, 234(5), 5451–5465. https://doi.org/10.1002/jcp.27486
Sioud, M. (2021). RNA Interference: Story and Mechanisms. Methods in Molecular Biology (Clifton, N.J.), 2282, 1–15. https://doi.org/10.1007/978-1-0716-1298-9_1
Sperling, R. (2019). Small non-coding RNA within the endogenous spliceosome and alternative splicing regulation. Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms, 1862(11–12), 194406. https://doi.org/10.1016/j.bbagrm.2019.07.007
Vilimova, M., & Pfeffer, S. (2023). Post-transcriptional regulation of polycistronic microRNAs. Wiley Interdisciplinary Reviews. RNA, 14(2), e1749. https://doi.org/10.1002/wrna.1749
Wajahat, M., Bracken, C. P., & Orang, A. (2021). Emerging Functions for snoRNAs and snoRNA-Derived Fragments. International Journal of Molecular Sciences, 22(19), 10193. https://doi.org/10.3390/ijms221910193
Webster, S. F., & Ghalei, H. (2023). Maturation of small nucleolar RNAs: From production to function. RNA Biology, 20(1), 715–736. https://doi.org/10.1080/15476286.2023.2254540
Wu, S. K., Roberts, J. T., Balas, M. M., & Johnson, A. M. (2020). RNA matchmaking in chromatin regulation. Biochemical Society Transactions, 48(6), 2467–2481. https://doi.org/10.1042/BST20191225
Conclusions
Dahan O, Gingold H & Pilpel Y (2011) Regulatory mechanisms and networks couple the different phases of gene expression. Trends Genet 27:316–322.
McManus, J., Cheng, Z., & Vogel, C. (2015). Next-generation analysis of gene expression regulation—Comparing the roles of synthesis and degradation. Molecular bioSystems, 11(10), 2680–2689. https://doi.org/10.1039/c5mb00310e