An overview of microRNAs

Discovered in 1980 in the nematode Caenorhabditis elegans, microRNAs (miRNAs) constitute a class of small non-coding RNA molecules of approximately 22 nucleotides in length that play a key role in post-transcriptional gene regulation either through translational repression and/or mRNA degradation. During their biogenesis, microRNA genes are firstly transcribed by RNA polymerase II as large primary transcripts (pri-miRNA) that are cut by the RNase III enzyme Drosha to yield the precursor miRNA (pre-miRNA); following Drosha processing, pre-miRNA is exported into the cytoplasm where maturation is completed upon cleavage by a second RNase III enzyme, Dicer. The ultimate fate of this mature miRNA of 22 nucleotides is to be loaded onto an AGO protein to form an effector complex called RNA-induced silencing complex (RISC). RISC guides the miRNA to mRNA targets in order to mediate translation repression. MiRNA maturation may be intrinsically regulated by the presence of single nucleotide polymorphisms (SNPs), RNA editing, methylation and tailing which alter RNA sequence and/or structure.

To date, more than 2000 miRNA have been discovered in humans and they are believed to collectively regulate 30% of the genes of the genome, thereby, contributing to a variety of biological processes such as development, differentiation, apoptosis, and cell proliferation. The expression profile of miRNAs appears to be cell-type specific and also disease-dependent.  Within the last decade, gene expression profiling studies have demonstrated an altered circulating miRNA expression across many human diseases and, in many cases, functional studies have linked miRNA dysregulation as a causal factor in disease progression. In fact, the detection of exosomes filled with miRNA has suggested that miRNA may also have a role in cell-to-cell communication. As for the cardiovascular system, robust evidence indicates that miRNAs are implicated in several pathological processes including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension, cardiac arrhythmias, vascular angiogenesis and cardiomyocyte apoptosis. Moreover, different panels of circulating miRNAs have been identified in blood of patients with different cardiovascular pathologies and have even shown to predict events (especially in the context of acute myocardial infarction and heart failure) raising the possibility that circulating miRNAs may also serve as potential biomarkers for prognosis and diagnosis of cardiovascular disease.

Currently, efforts are being focussed to develop miRNA-based therapies which mainly fall into two general categories: the miRNA mimics and the antisense oligonucleotide inhibitors. The first ones are addressed to replace the miRNAs found to be reduced in disease whereas the latter target those miRNAs that are found to be elevated. Yet, many barriers need to be overcome such as the mode of delivery, off-target effects, toxicity, immunological reaction and dosage determination, prior to their clinical therapeutic application.

Suggested further reading:

1. Thum T, Condorelli G. Circ Res. 2015; 116:751-62
2. van Rooij E, Kauppinen S. EMBO Mol Med. 2014; 6:851-64
3. van Rooij E. Circ Res. 2012; 110:481-258
4. Condorelli G, Latronico MV, Cavarretta E. J Am Coll Cardiol 2014; 63:2177-87