Decoys
Long non-coding RNAs (lncRNAs) are a kind of pervasive gene, which involves many biological functions. Many lncRNAs have been identified, and a variety of action modes have been proposed, such as signal, decoy, scaffold, guide, enhancer RNAs, and short peptides. When these RNAs are used as decoy molecules, they can bind and sequester proteins, thus inhibiting their normal functions.
Introduction of lncRNAs
The length of lncRNAs is more than 200 nucleotides, which exist in the nucleus and cytoplasm. Individual lncRNAs can be located in specific subcellular compartments, lacking protein-coding potential. The expression of lncRNA is usually regulated in a cell-specific way and plays a role in every step of gene expression, from chromatin remodeling, allele imprinting to post-transcriptional and post-translational processing. They are involved in a variety of biological processes, including neural and muscle development and immunity, and are related to human diseases, including cancer, neurodegenerative and muscle diseases. With the potential therapeutic options for regulating lncRNA in the form of antisense oligonucleotide (ASO) and other possible technologies, lncRNA based therapy may become an important healthcare strategy.
Figure 1. LncRNA classification based on genomic location. (Balas, 2018)
Decoy lncRNAs
The function of lncRNA as a decoy molecule is to titrate and regulate the proteins binding to lncRNA. It limits the availability of regulatory factors by presenting "decoy" binding sites. These lncRNAs modulate transcription by sequestering regulatory factors (including transcription factors, catalytic proteins, subunits of larger chromatin modified complexes and miRNAs), thus reducing their availability. Transcripts from lncRNA scaffolds play a structural role by providing a platform for the assembly of multicomponent complexes such as ribonucleoprotein (RNP) complexes. For RNP complex, once the complex is completely assembled, it can give transcriptional activation or inhibition according to the nature of existing protein and RNA.
Figure 2. Protein sequestration by lncRNAs. (Morriss, 2017)
Role of Decoy lncRNAs in Disease
LncRNA titration of proteins has a wide range of effects, affecting almost all steps of gene expression. Although decoy lncRNAs play a role in normal physiology, due to the destruction of normal function caused by protein sequestration, the RNA containing the allele expression of nucleotide repeat expansion may be pathogenic. The researchers discussed the commonness between decoy lncRNAs that competitively regulate gene expression. They inhibit the normal function of proteins by chelating or amplification of nucleotide repeats mediated by toxic RNA. The researchers discussed the commonness between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration. The abnormal amplification of nucleotide repeat sequences mediated by toxic RNA that sequesters RNA-binding proteins hinders their normal functions.
So far, 43 genetically-inherited nucleotide repeat disorders associated with single gene have been identified. These disorders usually cause disease by one or more of the following three mechanisms:
1) gain-of-function of toxic proteins translated from the extended nucleotide located in the coding regions of affected genes;
2) loss-of-function of proteins containing extended amino acid repeat sequences, or by affecting expression when the repeat expansion is located in the intronic or promoter regions;
3) toxic gain-of-RNA function from repeat expansions most often when located in non-coding regions of the affected gene.
Understanding how non-coding RNA binds to various RNA and DNA competitive regulatory proteins will provide insights into how similar mechanisms lead to disease pathogenesis and help guide future diagnosis and treatment options.
References
- Balas, M. M.; Johnson, A. M. (2018). Exploring the mechanisms behind long noncoding RNAs and cancer. Non-coding RNA research. 3(3): 108-117.
- Morriss, G. R.; Cooper, T. A. (2017). Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions. Human genetics. 136(9): 1247-1263.
