MicroRNAs are ~22-nucleotide single-stranded RNAs that inhibit the expression of specific mRNA targets through Watson–Crick base pairing between the miRNA ‘seed region’ and sequences commonly located in the 3′ untranslated regions (UTRs). The human genome is estimated to encode up to 1,000 miRNAs21
, which are either transcribed as standalone transcripts, frequently encoding several miRNAs, or generated by the processing of introns of protein-coding genes21
. The integration of miRNAs into introns of protein-coding genes serves to coordinate the expression of the miRNA with the mRNA encoded by that gene, without the necessity for a separate set of cis
-regulatory elements to drive expression of the miRNA (). It is not uncommon for intronic miRNAs to modulate the same biological processes as the protein encoded by the host gene22-26
. The dual functions of such genes, encoding protein and miRNA, provide sophisticated feedback and feedforward regulatory networks, specific examples of which are highlighted throughout this Review.
Genetic deletions of miRNAs in organisms ranging from worms to mice have shown that few developmental processes are absolutely dependent on single miRNAs8,27
. A recent study using compound mutant worms suggested there was significant redundancy within miRNA families, between unrelated miRNAs, and even between miRNAs and transcription factors, perhaps evolving as a buffer against deleterious variations in gene-expression programs28,29
. The actions of miRNAs often become pronounced under conditions of physiological or pathological signalling, suggesting conditional activities of miRNAs that necessitate genetic perturbation or sensitizing agents to uncover their functions.
miRNAs typically exert modest inhibitory effects on many mRNAs, which often encode proteins that govern the same biological process — for example, the fibrotic response is inhibited by miR-29 (ref. 14
), cardiac conduction by miR-1 (refs 30-32
), actin cytoskeletal dynamics by miR-145 (ref. 16
), the phosphatidylinositol-3-OH kinase (PI(3)K)–AKT pathway by miR-486 (ref. 33
) and stem-cell pluripotency by miR-145 (ref. 34
). The cumulative reduction in expression of several components of a molecular pathway reduces the importance of a single miRNA-mRNA interaction to elicit a biological response, and adds robustness to gene-regulatory networks (). The multiplicity of miRNA targets may also promote combinatorial regulation by miRNAs that individually target various mRNAs whose protein products contribute to one particular regulatory axis (). In this model, a biological response would be expected only after co-expression of several miRNAs that cooperatively target various components of a functional network or are all required to sufficiently repress a single target. By contrast, some miRNAs seem to reinforce an appropriately ‘balanced’ pathway by targeting both positive and negative regulatory components (for example, agonism and antagonism of Nodal signalling by miR-430)35
(). This mode of action allows buffering against minor physiological variations. Clearly, miRNA biology is a complex and highly orchestrated mode of gene regulation, potentially impinging on nearly all biological processes in mammals and having particularly important roles in disease states.