Competing endogenous RNA (ceRNA) is a group of different RNAs that compete with mRNA for the same pool of micro RNAs (miRNA). In doing this they regulate the ability of miRNA to inhibit mRNA from being translated into proteins.
The pool of ceRNA comprises different types of non-coding RNA (ncRNA), including long non-coding RNA (lncRNA), circular RNA (circRNA), and transcribed pseudogenes. They can bind miRNAs via miRNA response elements (MREs), acting as ‘sponge transcripts’ reducing the pool of miRNAs that is available to downregulate the translation of mRNAs.
Different studies have identified the role of ceRNA in different types of cells, including both healthy and diseased cells. The equilibrium between ceRNA and miRNA is important in the regulation of cancer and normal cell activity.
Mechanism of ceRNA activity
The theory of ceRNA as a regulator of miRNA activity was first conceptualized around 2010. Initial studies demonstrated this by overexpressing non-coding RNAs with concatamers to target sites on miRNA targets. This led to reduced miRNA function and increased levels of mRNA translation.
This has further been demonstrated in mammals and plants, indicating that ceRNA is important in miRNA regulation across eukaryotic species. It should also be noted that similar to mRNA, the degradation of many ceRNAs is mediated by miRNA activity.
In 2013 a group of researchers at Aarhus University in Denmark identified a strongly expressed circRNA, ciRS-7, which was known to be cleaved by the miRNA miR-671 but its function was unclear.
By searching MRE sites in ciRS-7, it was found to target miR-7, with which it forms a duplex. Crucially, in the middle section of the duplex, there is a mismatch in bases. This ensures that ciRS-7 can bind miR-7, inhibiting its activity, without being subject to miRNA mediated degradation itself.
miR-7 is found in many mammalian cells and likely has a significant role in the functioning of neurons. It has also been shown to be involved in certain cancer pathways and in Parkinson’s disease where it directly affects the expression of the α-synuclein protein. So understanding the role of ceRNA in regulating miR-7 activity may be key in future therapies for these diseases.
ceRNA in cardiovascular disease (CVD)
Aging is a major factor in CVD, as the cardiovascular system weakens with age it becomes increasingly vulnerable to heart attacks, thrombosis, etc. This can include weaker regulation of cellular processes and reduced structural integrity.
Recent evidence has linked several non-coding RNAs to such age-associated CVD. This is due to their role as regulators of inflammation, apoptosis, and cell growth, among others.
One example is the lncRNA, APF, which regulates the miRNA, miR-188-3p, in turn regulating the mRNA, ATG7. It is an important regulator of cell death and autophagy in cardiomyocytes, the sequestration of miR-188-3p by APF leads to increased translation of ATG7, subsequently leading to increased rates of autophagy.
An in vivo study, which silenced APF, showed that the reduced autophagy was associated with a lower myocardial infarction size. Less autophagy of heart cells would maintain the strength of the heart muscle, lowering the risk of infarction.
Another lncRNA, HOTAIR, has recently been investigated in a mouse model of diabetes. HOTAIR has been linked to the miRNA, miR-34a, which regulates the anti-aging factor SIRT1, known to repress inflammation.
In this model, overexpression of HOTAIR led to reduced infiltration of inflammatory cells into cardiac tissue. The associated increased levels of SIRT1 would have led to the promotion of anti-inflammatory pathways, reducing or inhibiting the recruitment of inflammatory immune cells.
Most potential therapies involving ceRNA would either look to restore the function of ncRNA that is under-expressed or inhibit the activity of overexpressed ncRNA. This could, for example, help to inhibit a pro-inflammatory pathway that increases the risk of CVD.
An important factor that may hamper any use of ceRNA in developing novel therapies is low conservation between species. While miRNA is highly conserved there is a high degree of variability in lncRNA sequences.
This could mean that animal models have limited use in understanding ceRNA/miRNA/mRNA networks that regulate translation.
Image Credit: igorstevanovic/Shutterstock.com
Conclusion
While some steps have been taken to understand ceRNA pathways, it is still a very new area and while some direct links to mRNA translation have been identified these pathways can be much more complex than some of the linear mechanisms described above.
Many ceRNAs can target two or more different miRNAs. So, where a ceRNA contains MREs for two different miRNAs there is competition for binding. The ceRNA may have a greater affinity for one miRNA over the other which would need to be taken into account in these complex pathways.
Further research in ceRNA may be essential in identifying potential therapies for certain cancers or other diseases. The upregulation of cancer pathways by some ceRNAs could mean that downregulating or sequestering certain ceRNAs helps to increase survival rates for some cancers.
References
- Greco, S., Gaetano, C. and Martelli, F. (2019) ‘Long noncoding competing endogenous RNA networks in age-associated cardiovascular diseases’, International Journal of Molecular Sciences. MDPI AG, p. 3079. doi: 10.3390/ijms20123079.
- Hansen, T. B. et al. (2013) ‘Natural RNA circles function as efficient microRNA sponges’, Nature, 495(7441), pp. 384–388. doi: 10.1038/nature11993.
- Sen, R. et al. (2014) ‘Competing Endogenous RNA: The Key to Posttranscriptional Regulation’, The Scientific World Journal. Hindawi Limited, 2014. doi: 10.1155/2014/896206.
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