Isoform Switching

Isoform switching

To enable our understanding of this concept, it is important to establish the fundamentals:

What are isoforms?

Isoforms are closely related proteins that originate from the same gene. However, they, sometimes differ functionally and structurally due to alternative splicing, variable promoter usage, and several other transcriptional modifications. According to Larochelle (2016), while isoforms function closely in related biochemical pathways, they can sometimes serve opposing effects on cellular processes in extreme conditions.

What is isoform switching?

Now that we know what isoforms are, we can move on to discuss isoform switching and its significance in medical research.

Isoform switching is simply the process whereby different isoforms of the same gene are expressed under various biological conditions. This process brings about a change in the way the gene encodes functional characteristics, as different isoforms carry out distinct functions. The process is biologically significant as it plays a role in development, and disease states. According to Wang et al. (2024), isoform switching plays an important role in cell fate determination. Furtheremore, in diseased states, like cancer, aberrant isoform switching is common.

Biological importance

• Cancer research

In a breast cancer study done by Zhao et al. (2016), the researchers identified genes that express multiple splice variants, including CD44, ESR1, ESR2, TP53, SYK, and BRCA1. The implication is that these genes are more susceptible to aberrant isoform switching as they produce several variants. The study suggested that investigation into alternative splicing events and their contribution to cancer development would provide a robust understanding of oncogenic processes and could potentially provide novel biomarkers (Zhao et al., 2016).

• Neurodegenerative disease research

Aberrant alternative splicing has been implicated in the pathogenesis of neurodegenerative diseases like Alzheimer’s disease. Under normal conditions, microtubule associated protein tau (MAPT) gene, which consists of 16 exons is alternatively spliced at exon 10. The exlusion of exon 10 forms the 3R tau, while its inclusion forms 4R tau. Imbalance between these isoforms causes tautopathies and AD pathogenesis as the 4R tau isoform plays major role in neurodegeneration than the 3R tau isoform (Mandelkow et al., 1996; Sealey et al., 2017).

These and many other areas highlight the significance of isoform switching research.

Conclusion

Understanding the processes that are involved in isoform switching is crucial for medical research because it allows scientists to investigate alternatively spliced genes and their functional outcomes. This knowledge can lead to the discovery of new biomarkers and the development of therapeutic strategies to address diseases caused by abnormal alternative splicing.

References

Larochelle, S. (2016). Protein isoforms: more than meets the eye. Nature Methods, 13(4), 291. https://doi.org/10.1038/nmeth.3828

Mandelkow, E. M., Schweers, O., Drewes, G., Biernat, J., Gustke, N., Trinczek, B., & Mandelkow, E. (1996). Structure, Microtubule Interactions, and Phosphorylation of Tau Protein a. Annals of the New York Academy of Sciences, 777(1), 96-106.

Sealey, M. A., Vourkou, E., Cowan, C. M., Bossing, T., Quraishe, S., Grammenoudi, S., Skoulakis, E. M., & Mudher, A. (2017). Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy. Neurobiology of Disease, 105, 74–83. https://doi.org/10.1016/j.nbd.2017.05.003

Wang, C., Shi, Z., Huang, Q., Liu, R., Su, D., Chang, L., Xiao, C., & Fan, X. (2024). Single-cell analysis of isoform switching and transposable element expression during preimplantation embryonic development. PLoS Biology, 22(2), e3002505. https://doi.org/10.1371/journal.pbio.3002505

Zhao, W., Hoadley, K. A., Parker, J. S., & Perou, C. M. (2016). Identification of mRNA isoform switching in breast cancer. BMC Genomics, 17(1). https://doi.org/10.1186/s12864-016-2521-9