Small Regulatory RNAs (siRNAs, microRNAs)
In recent years, RNA interference (RNAi) activation has developed as a widely used and powerful biological tool for functional annotation of the genome. Several variants of small regulatory RNA (srRNA) can trigger this highly conserved cellular pathway of evolution, leading to specific hybridization with target mRNA and subsequent degradation or translation inhibition.
srRNAs are non-coding RNA molecules that regulate genome structure and gene expression at many levels and fulfill functions in many aspects of cell life. srRNAs include microRNA, small interfering RNA (siRNA) and so on. They are unified through their association with Argonaute (AGO)-family proteins and their functions as regulatory RNAs that bind protein complexes to specific nucleic acid sequences. These small RNAs can exert regulation at the transcriptional level by affecting chromatin structure, or by affecting mRNA stability or translation after transcription.
Figure 1. Regulatory networks involving small non-coding RNAs. (Mattick, 2005)
siRNA
siRNA is derived from long double-stranded RNA molecules (including RNA produced by viral replication, transposon activity or gene transcription). It can be cut by the Dicer enzyme into 19-24 nt RNA fragments, which play their role when loaded on AGO protein. Recent studies have shown that siRNA can induce intracellular transcriptional gene silencing through DNA methylation and histone modification.
microRNA
miRNAs are single-stranded RNAs, about 19-24 nt, 50% of which are located in the region of chromosome structure. Unlike siRNA, miRNA is endogenous, the expression product of biological genes, and is composed of incomplete hairpin-like double-stranded RNA, which is jointly processed by Drosha and Dicer. Recently, nearly 1800 hypothetical miRNAs have been found in the human genome, and the number of miRNAs is still increasing rapidly due to the development of high-throughput sequencing technology. In-depth study of the regulatory mechanism and role of miRNA will help to clarify the mechanism of tumor occurrence and broaden our vision of a new target for disease treatment.
Figure 2. Non-coding RNAs as regulators in epigenetics. (Wei, 2017)
srRNAs in Mammals
Mammalian cells contain a large number of non-protein-coding RNAs, which regulate gene expression including chromatin structure, RNA editing, RNA stability, translation, and quite possibly transcription and splicing. They are processed by multiple pathways from introns and exons of long original transcripts (including protein-coding transcripts). Depending on the mode of activation, RNA-processing and efficacy as well as the dynamics of RNAi may vary from transient effects to persistent gene silencing. Homology-dependent gene silencing by srRNAs at the post-transcriptional level provides a powerful and relatively easy-to-use strategy to study gene function in many biological systems.
Moreover, many phenotypic variations in mammals and other complex organisms may have different genetic characteristics from the sequences encoding proteins. This may be due to the extensive regulatory network of non-coding RNA based on signal transduction. These non-coding srRNAs control a wide range of development and physiological pathways in animals, including hematopoietic differentiation, adipocyte differentiation and mammalian insulin secretion, and interference with cancer and other diseases.
srRNAs in Bacteria
srRNAs are the most abundant post-transcriptional regulators in bacteria. They are usually 50-500 bp long and encoded about 200-300 copies in a typical bacterial genome. srRNAs can directly or indirectly regulate most bacterial genes, either by degrading mRNA or masking ribosome binding sites to inhibit the translation of mRNA, or by opening ribosome binding sites or improving the stability of mRNA to activate translation.
They are involved in many processes of bacterial cells, including quorum sensing, stress response, toxicity and carbon metabolism, through various mechanisms such as RNA conformational changes, protein binding, base pairing with other RNA and interaction with DNA. Therefore, they play an important role in cell physiology and bacterial pathogenesis, opening up a new field for molecular biology.
Figure 3. Gene arrangement and regulatory functions of ligand- and protein-binding srRNAs. (Waters, 2009)
References
- Mattick, J. S.; Makunin, I. V. (2005). Small regulatory RNAs in mammals. Human molecular genetics. 14(suppl_1): R121-R132.
- Wei, J. W.; et al. (2017). Non-coding RNAs as regulators in epigenetics. Oncology reports. 37(1): 3-9.
- Waters, L. S.; Storz, G. (2009). Regulatory RNAs in bacteria. Cell. 136(4): 615-628.
