Therapy Analysis - microRNA
What is microRNA?
These sequences are produced within the cell by transcription from individual miRNA genes, from introns within protein genes, or from polycistronic clusters of closely related miRNA genes. The initial transcripts, ‘pri-miRNAs’, are several thousand bases long. These are then processed within the nucleus by a ‘microprocessor complex’ containing a double-stranded RNA-specific ribonuclease known as Drosha, and its binding partner Pasha, to give hairpin RNA precursors known as ‘pre-miRNAs’, which are then transported to the cytoplasm using Exportin-5. Cleavage by the endonuclease Dicer results in a double-stranded miRNA, which is then incorporated into an RNA-induced silencing complex (RISC), similar to that involved in the related (but distinct) process of RNA interference. Once there, a single mature miRNA strand is selected and the other is degraded, and the mature strand is then in a position to manipulate gene expression (Fig 1).
The resulting active miRNAs down-regulate gene expression by translational repression and/or messenger RNA (mRNA) cleavage, mediated by the RISC, in a manner strikingly similar to the much-documented gene silencing/RNA interference effects of agents such as short interfering RNA (siRNA). However, although siRNAs also silence expression via RISC, there are some crucial differences from miRNAs. For instance, naturally-occurring siRNAs have not been documented in mammals, in contrast to the wide prevalence of endogenous miRNAs. And most notably, siRNAs are highly complementary to their target gene transcripts, whereas miRNAs are not – in fact, miRNAs only have complementarity in a crucial ‘seed’ region 2-8 bases long in the 5’ region. This can make it possible for some miRNAs to pair with hundreds of high- and low-affinity mRNA targets (one-to-many), and conversely, multiple miRNAs may target a single mRNA (many-to-one). Thus, the precise one-to-one specificities of siRNAs for their targets can be contrasted with much more far-reaching effects of a single miRNA on expression of many genes, with some individual miRNAs affecting entire pathways or disease mechanisms.
This intriguing natural mechanism seems to be a very ancient one in evolution, having been detected throughout plant and animal systems in various forms, and even in viruses. The sequences involved appear to be highly conserved between individuals and indeed species, but their populations and compositions within cells correlate very strongly with specific cell or tissue types, developmental stages and/or disease states. Thus, profiling of these populations as biomarkers should be a very powerful diagnostic and prognostic tool, and the technology for detecting and analyzing miRNAs within cells has already advanced rapidly to accommodate this possibility, with notable successes in the profiling of metastatic cancers. But what about their implications as therapeutic targets? To answer that, one must consider their natural function and how it may be exploited.
