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The stem-loop secondary structure of a pre-microRNA from Brassica oleracea.

In genetics, microRNAs (miRNA or μRNA) are single-stranded RNA molecules of 21-23 nucleotides in length, which regulate gene expression. miRNAs are encoded by genes from whose DNA they are transcribed but miRNAs are not translated into protein (i.e. they are non-coding RNAs); instead each primary transcript (a pri-miRNA) is processed into a short stem-loop structure called a pre-miRNA and finally into a functional miRNA. Mature miRNA molecules are either fully or partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to down-regulate gene expression. miRNAs were first described in 1993 by Lee and colleagues in the Victor Ambros lab [1], but the term microRNA was only introduced in 2001 in a set of three articles in Science.[2]

Contents

[edit] Formation and processing

MicroRNAs are produced from either their own genes or from introns

MicroRNAs can be encoded by independent genes, but also be processed (via the enzyme Dicer) from a variety of different RNA species, including introns, 3' UTRs of mRNAs, long noncoding RNAs, snoRNAs and transposons.[3][4][5]

The genes encoding miRNAs are much longer than the processed mature miRNA molecule; miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus. This processing is performed in animals by a protein complex known as the Microprocessor complex, consisting of the nuclease Drosha and the double-stranded RNA binding protein Pasha.[6] These pre-miRNAs are then processed to mature miRNAs in the cytoplasm by interaction with the endonuclease Dicer, which also initiates the formation of the RNA-induced silencing complex (RISC).[7] This complex is responsible for the gene silencing observed due to miRNA expression and RNA interference. The pathway in plants varies slightly due to their lack of Drosha homologs; instead, Dicer homologs alone effect several processing steps.[8] The pathway is also different for miRNAs derived from intronic stem-loops; these are processed by Dicer but not by Drosha.[9] Either the sense strand or antisense strand of DNA can function as templates to give rise to miRNA.[10]

Efficient processing of pri-miRNA by Drosha requires the presence of extended single-stranded RNA on both 3'- and 5'-ends of hairpin molecule.[11] These ssRNA motifs could be of different composition while their length is of high importance if processing is to take place at all. A bioinformatics analysis of human and fly pri-miRNAs revealed very similar structural regions, called 'basal segments', 'lower stems', 'upper stems' and 'terminal loops'; based on these conserved structures, thermodynamic profiles of pri-miRNA have been determined.[12] The Drosha complex cleaves the RNA molecule ~22 nucleotides away from the terminal loop.[13] Most pre-miRNAs don't have a perfect double-stranded RNA (dsRNA) structure topped by a terminal loop. There are few possible explanations for such selectivity. One could be that dsRNAs longer than 21 base pairs activate interferon response and anti-viral machinery in the cell. Another plausible explanation could be that the thermodynamic profile of pre-miRNA determines which strand will be incorporated into Dicer complex. Indeed, clear similarities between pri-miRNAs encoded in respective (5'- or 3'-) strands have been demonstrated.[12]

When Dicer cleaves the pre-miRNA stem-loop, two complementary short RNA molecules are formed, but only one is integrated into the RISC. This strand is known as the guide strand and is selected by the argonaute protein, the catalytically active RNase in the RISC, on the basis of the stability of the 5' end.[14] The remaining strand, known as the miRNA*, anti-guide or passenger strand, is degraded as a RISC substrate.[15][16] After integration into the active RISC, miRNAs base pair with their complementary mRNA molecules and inhibit translation or sometimes induce mRNA degradation by argonaute proteins, the catalytically active members of the RISC [17]. It is as yet unclear how the activated RISC locates the mRNA targets in the cell, though it has been shown that the process is not coupled to ongoing protein translation from the mRNA.[18]

[edit] Turnover of mature microRNAs

miRNA biogenesis is highly regulated. It is controlled at both transcriptional and post-transcriptional levels. Overexpression and underexpression are linked to various human diseases, especially cancers. An additional layer of regulation of animal miRNA activity is important for rapid changes of miRNA expression profiles. Degradation of mature miRNAs is mediated by the 5´-->3´ exoribonuclease XRN2.[19]

[edit] Cellular functions

The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is complementary to a part of one or more messenger RNAs (mRNAs). Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs.[20] Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA.[21] This is the primary mode of plant microRNAs.[22] In animals, microRNAs more often only partially base pair and inhibit protein translation of the target mRNA[23] (this exists in plants as well but is less common).[22] MicroRNAs that are partially complementary to the target can also speed up deadenylation, causing mRNAs to be degraded sooner.[24] For partially complementary microRNA to recognise their targets, the nucleotides 2–7 of the miRNA ('seed region'), still have to be perfectly complementary.[25] miRNAs occasionally also causes DNA methylation of promoter sites and therefore affecting the expression of targeted genes.[26][27] miRNAs function in association with a complement of proteins collectively termed the miRNP. Human miRNPs contain eIF2C2 (also known as Argonaute 2), DDX20, GEMIN4 and microRNA.[28]

Animal microRNAs target in particular developmental genes. In contrast, genes involved in functions common to all cells, such as gene expression, have very few microRNA target sites, and seem to be under selection to avoid targeting by microRNAs.[29]

This effect was first described for the worm C. elegans in 1993 by Victor Ambros and coworkers.[1] As of 2002, miRNAs have been confirmed in various plants and animals, including C. elegans, human and the plant Arabidopsis thaliana. Work at the University of Louisville has resulted in the production of microarrays dubbed MMChips containing all then known miRNAs for human, mouse, rat, dog, C. elegans and Drosophila.[30] Agilent has subsequently commercialized a human miRNA microarray.[31]

Mirtrons are the type of microRNAs which are located in the introns of the mRNA encoding host genes. All the miRNAs in plants are derived from the sequential DCL1 cleavages from pri-miRNA to give pre-miRNA (or miRNA precursor). But the mirtrons bypass the DCL1 cleavage and enter as pre-miRNA in the miRNA maturation pathway.

[edit] Gene activation

dsRNA can also activate gene expression, a mechanism that has been termed "small RNA-induced gene activation" or RNAa. dsRNAs targeting gene promoters can induce potent transcriptional activation of associated genes. This was demonstrated in human cells using synthetic dsRNAs termed small activating RNAs (saRNAs),[32] but has also been demonstrated for endogenous microRNA.[33]

[edit] Experimental detection and manipulation of miRNA

MicroRNA expression can be quantified by modified RT-PCR followed by QPCR[34], or profiled against a database describing thousands of known miRNAs using microarray technology.[35] The activity of an miRNA can be experimentally inhibited using a locked nucleic acid oligo, a Morpholino oligo[36][37] or a 2'-O-methyl RNA oligo.[38] MicroRNA maturation can be inhibited at several points by steric-blocking oligos.[39] The miRNA target site of an mRNA transcript can also be blocked by a steric-blocking oligo[40][41]. Additionally, a specific miRNA can be silenced by a complementary antagomir.

[edit] Genomics of microRNA

It was initially thought that miRNA genes were located in intergenic regions, however, later study showed that several miRNA genes were located within introns of either protein-coding or noncoding genes, or in intergenic regions, while only a few were located in exons of noncoding RNAs or UTR of protein coding genes. [42] Recently, it has been shown that miRNA genes overlap with the protein-coding region of the genes of a multigene family. [43]

[edit] miRNA and disease

Just as miRNA is involved in the normal functioning of eukaryotic cells, so has dysregulation of miRNA been associated with disease. Disease association in turn has led to increased funding opportunities for academic research and financial incentives for development and commercialization of miRNA-based diagnostics and therapeutics. After early commercialization aimed at academic research support was established, the initial research focus based on products and services requested was on cancer and neuroscience research. During 2007, interests indicated by product and services requested broadened to include cardiac research, virology, cell biology in general and plant biology.[30] A manually curated database miR2Disease that aims at documenting known relationships between miRNA dysregulation and human disease is publicly available. [44]

[edit] miRNA and cancer

Several miRNAs has been found to have links with some types of cancer.

A study of mice altered to produce excess c-myc — a protein implicated in several cancers — shows that miRNA has an effect on the development of cancer. Mice that were engineered to produce a surplus of types of miRNA found in lymphoma cells developed the disease within 50 days and died two weeks later. In contrast, mice without the surplus miRNA lived over 100 days.[45] Leukemia can be caused by the insertion of a virus next to the the 17-92 array of microRNAs leading to increased expression of this microRNA.[46]


Another study found that two types of miRNA inhibit the E2F1 protein, which regulates cell proliferation. miRNA appears to bind to messenger RNA before it can be translated to proteins that switch genes on and off.[47]

By measuring activity among 217 genes encoding miRNA, patterns of gene activity that can distinguish types of cancers can be discerned. miRNA signatures may enable classification of cancer. This will allow doctors to determine the original tissue type which spawned a cancer and to be able to target a treatment course based on the original tissue type. miRNA profiling has already been able to determine whether patients with chronic lymphocytic leukemia had slow growing or aggressive forms of the cancer.[48] In 2008, the companies Asuragen and Exiqon were working to commercialize this potential for miRNAs to act as cancer biomarkers.[30][49]

[edit] miRNA and heart disease

The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the murine heart, and has revealed that miRNAs play an essential role during its development.[50][51] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[52][53][54] Furthermore, studies on specific miRNAs in animal models have identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response, and cardiac conductance.[51][55][56][57][58][59] In 2008, academic work on the relationship between miRNA and heart disease had advanced sufficiently to lead to the establishment of a company, miRagen Therapeutics, with a primary focus on "cardiovascular health and disease".[30]

[edit] Other conditions

One study implicates miRNA as a factor in the development of schizophrenia.[60]

[edit] References

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[edit] Further reading

  • This paper discusses the role of microRNAs in viral oncogenesis: Scaria V (2007). "microRNAs in viral oncogenesis.". Retrovirology 4 (82): 68. doi:10.1186/1742-4690-4-82. 
  • This paper discusses the role of microRNAs in Host-virus interactions: Scaria V (2006). "Host-Virus Interaction: A new role for microRNAs.". Retrovirology 3 (1): 68. doi:10.1186/1742-4690-3-68. PMID 17032463. 
  • This paper defines miRNA and proposes guidelines to follow in classifying RNA genes as miRNA: Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, Griffiths-Jones S, Marshall M, Matzke M, Ruvkun G, Tuschl T (2003). "A uniform system for microRNA annotation". RNA 9 (3): 277–279. doi:10.1261/rna.2183803. PMID 12592000. 
  • This paper discusses the processes that miRNA and siRNAs are involved in, in the context of 2 articles in the same issue of the journal Science: Baulcombe D (2002). "DNA events. An RNA microcosm.". Science 297 (5589): 2002–2003. doi:10.1126/science.1077906. PMID 12242426. 
  • This paper describes the discovery of lin-4, the first miRNA to be discovered: Lee RC, Feinbaum RL, Ambros V (1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell 75 (5): 843–854. doi:10.1016/0092-8674(93)90529-Y. PMID 8252621. 

[edit] External links

[edit] See also

v • d • e
Types of RNA
Protein synthesis
RNA processing
Gene regulation
Cis-regulatory elements
Parasites
Other
v • d • e
Types of nucleic acids
Constituents
Ribonucleic acids
(coding and non-coding)

translation: mRNA (pre-mRNA/hnRNA) · tRNA · rRNA · tmRNA

regulatory: miRNA · siRNA · piRNA · aRNA

RNA processing: snRNA · snoRNA

other/ungrouped: gRNA · shRNA · stRNA · ta-siRNA
Deoxyribonucleic acids
cDNA · cpDNA · gDNA · msDNA · mtDNA
Nucleic acid analogues
GNA · LNA · PNA · TNA · morpholino
Cloning vectors
phagemid · plasmid · lambda phage · cosmid · P1 phage · fosmid · BAC · YAC · HAC
Major families of biochemicals
Saccharides/Carbohydrates/Glycosides · Amino acids/Peptides/Proteins/Glycoproteins · Lipids/Terpenes/Steroids/Carotenoids · Alkaloids/Nucleobases/Nucleic acids · Cofactors/Phenylpropanoids/Polyketides/Tetrapyrroles
Retrieved from "http://en.wikipedia.org/wiki/MicroRNA"



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