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MicroRNA

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

In genetics, microRNAs (miRNA) 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 (non-coding RNA); 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 partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to down-regulate gene expression. They were first described in 1993 by Lee and colleagues in the Victor Ambros lab [1], yet the term microRNA was only introduced in 2001 in a set of three articles in Science.[2]

Formation and processing

MicroRNA (miRNA) is produced from precursor microRNA (pre-miRNA), which in turn is formed from a microRNA primary transcript (pri-miRNA).

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.[3] 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).[4] 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.[5] The pathway is also different for miRNAs derived from intronic stem-loops; these are processed by Dicer but not by Drosha.[6] Either the sense strand or antisense strand of DNA can function as templates to give rise to miRNA.[7]

Efficient processing of pri-miRNA by Drosha requires the presence of extended single-stranded RNA on both 3'- and 5'-ends of hairpin molecule.[8] 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.[9] The Drosha complex cleaves the RNA molecule ~22 nucleotides away from the terminal loop.[10] 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.[9]

When Dicer cleaves the pre-miRNA stem-loop, two complementary short RNA molecules are formed, but only one is integrated into the RISC complex. This strand is known as the guide strand and is selected by the argonaute protein, the catalytically active RNase in the RISC complex, on the basis of the stability of the 5' end.[11] The remaining strand, known as the anti-guide or passenger strand, is degraded as a RISC complex substrate.[12] After integration into the active RISC complex, 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 complex[13]. It is as yet unclear how the activated RISC complex 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.[14]

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. The annealing of the miRNA to the mRNA then inhibits protein translation, but sometimes facilitates cleavage of the mRNA. This is thought to be the primary mode of action of plant miRNAs. In such cases, the formation of the double-stranded RNA through the binding of the miRNA triggers the degradation of the mRNA transcript through a process similar to RNA interference (RNAi), though in other cases it is believed that the miRNA complex blocks the protein translation machinery or otherwise prevents protein translation without causing the mRNA to be degraded. miRNAs may also target methylation of genomic sites which correspond to targeted mRNAs. miRNAs function in association with a complement of proteins collectively termed the miRNP.

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 containing all known (at the time of production) miRNAs for human, mouse, rat, dog, C. elegans and Drosophila species, tools referred to as MMChips.[15] Agilent has subsequently commercialized a human miRNA microarray.[16]

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),[17] but has also been demonstrated for endogenous microRNA.[18]

Detecting and manipulating miRNA signaling

The activity of an miRNA can be experimentally blocked using a locked nucleic acid oligo, a Morpholino oligo[19][20] or a 2'-O-methyl RNA oligo.[21] Steps in the maturation of miRNAs can be blocked by steric-blocking oligos.[22] The target site of an miRNA on an mRNA can be blocked by a steric blocking oligo[23][24].

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.[15]

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.[25]

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.[26]

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.[27] In 2008, the companies Asuragen and Exiqon were working to commercialize this potential for miRNAs to act as cancer biomarkers.[15][28]

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.[29][30] miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in cardiomyopathies.[31][32][33] 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.[30][34][35][36][37][38] In 2008, academic work on the relationship between miRNA and heart disease had advanced sufficiently to lead to the establishment of a company, miRagen, with a primary focus on "cardiovascular health and disease".[15]

References

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  2. ^ Ruvkun G (2001). "Molecular biology. Glimpses of a tiny RNA world". Science (journal). 294 (5543): 797–9. doi:10.1126/science.1066315. PMID 11679654. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004). "Processing of primary microRNAs by the Microprocessor complex". Nature. 432 (7014): 231–5. doi:10.1038/nature03049. PMID 15531879. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  20. ^ Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG (2007). "Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate". Nat. Genet. 39 (2): 259–63. doi:10.1038/ng1953. PMID 17220889. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  22. ^ Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RH (2007). "Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development". PLoS Biol. 5 (8): e203. doi:10.1371/journal.pbio.0050203. PMC 1925136. PMID 17676975. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  23. ^ Choi, WY (2007). "Target Protectors Reveal Dampening and Balancing of Nodal Agonist and Antagonist by miR-430" (Pubmed). Science. PMID 17761850. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  24. ^ Klein, ME (2007). "Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA" ([dead link] – Scholar search). Nature Neuroscience. 10: 1513. doi:10.1038/nn2010. {{cite journal}}: External link in |format= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  25. ^ He L, Thomson JM, Hemann MT; et al. (2005). "A microRNA polycistron as a potential human oncogene". Nature. 435 (7043): 828–33. doi:10.1038/nature03552. PMID 15944707. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

See also

External links

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