Non-coding RNAs (ncRNAs) are RNA molecules that are transcribed from DNA but are not translated into proteins; instead, they function directly as RNA. Their primary role lies in gene regulation, where they can modulate gene expression at various levels, including transcription, post-transcriptional processing, and translation.
Among the diverse ncRNA family, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as key players, demonstrating mechanisms adapted to control gene expression in higher organisms. LncRNAs, exceeding 200 nucleotides, can act as scaffolds or RNA-protein multicomplex guides, while circRNAs can sponge microRNAs with higher functional stability.
But, how do lncRNAs and circRNAs precisely modulate cellular functions and contribute to the complex mechanisms underlying diseases?
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Understanding lncRNAs and circRNAs
Long non-coding RNAs (lncRNAs) are RNA transcripts exceeding 200 nucleotides in length that, unlike mRNAs, are not translated into proteins. They exhibit diverse functions in gene regulation, operating at both transcriptional and post-transcriptional levels.
At the transcriptional level, lncRNAs can recruit chromatin-modifying complexes to specific genomic loci, while post-transcriptionally, they can affect mRNA splicing, stability, and translation.
Circular RNAs (circRNAs) are covalently closed, highly stable, RNA loops generated through back-splicing, a distinct biogenesis process that those involved in the generation of lncRNA linear molecules.
CircRNAs primarily function as sponges for microRNAs (miRNAs), another class of regulatory non-coding RNA that is well-known for recently winning a Nobel Prize (awarded to Victor Ambros and Gary Ruvkun), sequestering and preventing them from targeting their mRNA targets.
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Mechanisms of Action in Gene Regulation
LncRNAs exert multifaceted regulatory functions, serving as chromatin modifiers by recruiting complexes that alter histone modifications and, thus, gene accessibility.
They can also act as transcriptional enhancers by guiding transcription factors to specific DNA sequences or as molecular decoys by sequestering proteins or RNAs, preventing their normal interactions.
A previously underappreciated function of lncRNAs is their processing into smaller, functional RNA species. Emerging evidence indicates that lncRNAs can also serve as precursors for smaller regulatory RNAs (i.e., siRNAs or miRNAs), acting as precursors for small ncRNA biogenesis.
These small RNAs can in turn modulate gene expression at specific loci through both repressive and activating mechanisms1. This form of gene regulation is observed across a broad spectrum of higher organisms, from plants to animals, including humans.
Moreover, circRNAs primarily operate as competitive endogenous RNAs (ceRNAs), effectively "sponging" miRNAs and thereby modulating miRNA-mediated gene expression pathways.
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Role in Health and Disease
LncRNAs have been implicated in both disease states and normal development. For instance, HOX antisense intergenic RNA (HOTAIR) is a lncRNA that regulates gene expression and chromatin dynamics.
It has been implicated in cancer progression through diverse mechanisms, including the promotion of cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), suggesting its inhibition as a potential therapeutic strategy. High HOTAIR expression in breast cancer cells enhances metastatic capacity and invasiveness, further supporting the potential of HOTAIR targeting to mitigate breast cancer2.
Moreover, increased HOTAIR expression in tumor tissues strongly correlates with lymph node metastasis in patients with triple-negative breast cancer, a well-known type of breast cancer where the cancer cells lack receptors for estrogen, progesterone, and the HER2 protein3.
Similarly, circRNAs have also been shown to play roles in human diseases, including cancer, diabetes, cardiovascular, and neurodegenerative diseases. Their high stability and tissue specificity make them potential biomarkers for disease course and treatment efficacy4.
For instance, circRNAs show potential as potent biomarkers with diagnostic, prognostic, and therapeutic value for ovarian cancer, potentially influencing cell proliferation, apoptosis, metastasis, and chemotherapy resistance5.
Moreover, circRNA’s involvement in gene regulation, cardiac function improvement, and modulation of pathways related to cardiac repair and fibrosis suggests a potential role in myocardial infarction (MI). Researchers recently discovered one circRNA (hsa_circ_010567) that regulates the miRNA miR-141, thereby exerting a protective effect against cardiomyocyte damage6.
This role of circRNAs in cardiac diseases is particularly pertinent to elucidating the cardiac effects of emerging diseases like COVID-19. circACSL1 is a circRNA capable of exacerbating myocardial inflammation and injury by sponging miR-8055, thereby regulating the well-known mitogen-activated protein kinase 14 protein (MAPK14), involved in cellular responses to inflammation and environmental stress7.
Intriguingly, the miRNA miR-8055, partially investigated due to its sequence complementarity with a region of the SARS-CoV-2 spike protein, may potentially be associated with the established myocardial effects of COVID-198.
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Challenges and Future Directions
Identifying and characterizing functional non-coding RNAs (ncRNAs) presents significant technical challenges due to their low expression levels, tissue-specific expression patterns, and complex secondary structures.
Advances in RNA sequencing technologies, such as long-read sequencing and single-cell RNA-seq, coupled with sophisticated computational tools for data analysis, are overcoming technical hurdles. Such advancements are expected to aid in the development of RNA-based therapies, which can precisely target and modulate ncRNA activity.
Conclusion
LncRNAs and circRNAs have emerged as crucial regulators of gene expression, influencing diverse mechanisms at both transcriptional and post-transcriptional levels. Their functional versatility positions them as promising targets for precision medicine, offering the potential for tailored diagnostics and therapeutics.
Given their easy detectability and stability (especially circRNAs), they hold significant promise as biomarkers, and their ability to modulate gene expression opens avenues for novel RNA-based therapies.
Further research is needed to fully elucidate the roles of ncRNAs in complex diseases, helping to develop innovative diagnostic tools and therapeutic interventions that can revolutionize biological fields.
References
- Vaschetto, L. M. (2018). miRNA activation is an endogenous gene expression pathway. RNA biology, 15(6), 826-828.
- Qing Ma et al. "Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis." eLife, 11 (2022). https://doi.org/10.7554/eLife.79126.
- Collina, F., Aquino, G., Brogna, M., Cipolletta, S., Buonfanti, G., De Laurentiis, M., Di Bonito, M., Cantile, M., & Botti, G. (2019). LncRNA HOTAIR up-regulation is strongly related with lymph nodes metastasis and LAR subtype of Triple Negative Breast Cancer. Journal of Cancer, 10, 2018 - 2024. https://doi.org/10.7150/jca.29670.
- Verduci, L., Tarcitano, E., Strano, S., Yarden, Y., & Blandino, G. (2021). CircRNAs: role in human diseases and potential use as biomarkers. Cell Death & Disease, 12. https://doi.org/10.1038/s41419-021-03743-3.
- Foruzandeh, Z., Zeinali-Sehrig, F., Nejati, K., Rahmanpour, D., Pashazadeh, F., Seif, F., & Alivand, M. (2021). CircRNAs as potent biomarkers in ovarian cancer: a systematic scoping review. Cellular & Molecular Biology Letters, 26. https://doi.org/10.1186/s11658-021-00284-7.
- Bai, M., Cl, P., Gx, J., & Ym, Z. (2020). CircRNA 010567 improves myocardial infarction rats through inhibiting TGF-β1.. European review for medical and pharmacological sciences, 24 1, 369-375. https://doi.org/10.26355/eurrev_202001_19935.
- Zhang, L., Han, B., Liu, H., Wang, J., Feng, X., Sun, W., ... & Jiang, D. (2021). Circular RNA circACSL1 aggravated myocardial inflammation and myocardial injury by sponging miR-8055 and regulating MAPK14 expression. Cell Death & Disease, 12(5), 487.
- Vaschetto, L. A putative miRNA in the spike gene of SARS-CoV-2 has perfect sequence identity to both the forward and reverse complementary strands of hsa-mir-8055 involved in T-cell response to antigen. OSF Preprints 2020.
Further Reading