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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 about 21-23 nucleotides in length thought to regulate the expression of other genes. miRNAs are encoded by genes that are transcribed from DNA but not translated into protein (non-coding RNA); instead they are processed from primary transcripts known as pri-miRNA to short stem-loop structures called pre-miRNA and finally to functional miRNA. Mature miRNA molecules are partially complementary to 3' or 5' UTR of one or more messenger RNA (mRNA) molecules, which they function as to downregulate expression.

The term miRNA was first introduced in a set of three articles in Science (26 October 2001)[1]

Formation and processing

The genes encoding miRNAs are much longer than the processed miRNA molecule; miRNAs are first transcribed as primary transcripts or pri-miRNA 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.[2] 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).[3] 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.[4]

Zeng et al. have shown that efficient processing of pre-miRNA by Drosha requires presence of extended single-stranded RNA on both 3'- and 5'-ends of hairpin molecule. They demonstrated that these motifs could be of different composition while their length is of high importance if processing is to take place at all. Their findings were confirmed in another work by Han et al. Using bioinformatical tools Han et al. analysed folding of 321 human and 68 fly pri-miRNAs. 280 human and 55 fly pri-miRNAs were selected for further study, excluding those molecules which folding showed presence of multiple loops. All human and fly pri-miRNA contained very similar structural regions, which authors called 'basal segments', 'lower stem', 'upper stem' and 'terminal loop'. Based on the encoding position of miRNA, i.e. in the 5'-strand (5'-donors) or 3'-strand (3'-donors), thermodynamical profiles of pri-miRNA was determined. Following experiments have shown that Drosha complex cleaves RNA molecule ~2 helical turns away from the terminal loop and ~1 turn away from basal segments. In most analysed molecules this region contain unpaired nucleotides and the free energy of the duplex is relatively high compared to lower and upper stem regions.

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 11 base pairs activate interferon response and anti-viral machinery in the cell. Another plausible explanation could be that thermodynamical profile of pre-miRNA determines which strand will be incorporated into Dicer complex. Indeed, aforementioned study by Han et al. demonstrated very clear similarities between pri-miRNAs encoded in respective (5'- or 3'-) strands.

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.[5] The remaining strand, known as the anti-guide or passenger strand, is degraded as a RISC complex substrate.[6] After integration into the active RISC complex, miRNAs base pair with their complementary mRNA molecules and induce mRNA degradation by argonaute proteins, the catalytically active members of the RISC complex. 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.[7]

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 Caenorhabditis elegans in 1993 by R. C. Lee of Harvard University. As of 2002, miRNAs have been confirmed in various plants and animals, including C. elegans, human and the plant Arabidopsis thaliana. Genes have been found in bacteria that are similar in the sense that they control mRNA abundance or translation by binding an mRNA by base pairing, however they are not generally considered to be miRNAs because the Dicer enzyme is not involved.

In plants, similar RNA species termed short-interfering RNAs siRNAs are used to prevent the transcription of viral RNA. While this siRNA is double-stranded, the mechanism seems to be closely related to that of miRNA, especially taking the hairpin structures into account. siRNAs are also used to regulate cellular genes, as miRNAs do.

Detecting and manipulating miRNA signalling

The activity of an miRNA can be experimentally blocked using a locked nucleic acid oligo, a Morpholino oligo[8] [9]or a 2'-O-methyl RNA oligo. [10]Most efficient methods for miRNA detection are based on oligonucleotides modified with locked nucleic acids.[11]

Regulation

microRNA regulation has a major impact on the proper regulation of a cell, and thus of the organism. Studies in which parts of the microRNA processing machinery have been knocked out indicate that an organism can not survive in its absence. Less well known is the impact of individual microRNAs on their target genes. This is because target prediction is complicated. However, it is likely that microRNAs function similar to transcription factors. Their impact on target regulation can vary from minor to significant depending on a variety of factors. A report from May 2006 examined the level of control exerted by a microRNA specific for hematopoietic cells [12]. The work indicated that a single microRNA could delineate gene expression between cells of hematopoietic and non-hematopoietic lineages in mice. This work offers indirect, but important proof of the potential regulatory impact a microRNA can have on gene regulation.

miRNA and cancer

miRNA 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.[13]

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.[14]

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.[15]

References

  1. ^ Ruvkun, G. (2001). "Molecular biology. Glimpses of a tiny RNA world". Science. 294 (5543): 797–9. PMID: 11679654. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. (2004). Nature 432(7014):231-5.
  3. ^ Bernstein E, Caudy AA, Hammond SM, Hannon GJ. (2001). Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363-6.
  4. ^ Kurihara Y, Watanabe Y. (2004). Arabidopsis micro-RNA biogenesis through Dicer-like 1 protein functions. Proc Natl Acad Sci USA 101(34):12753-8.
  5. ^ Preall JB, He Z, Gorra JM, Sontheimer EJ. (2006). Short interfering RNA strand selection is independent of dsRNA processing polarity during RNAi in Drosophila. Curr Biol 16(5):530-5.
  6. ^ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. (2005). Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123(4):631-40.
  7. ^ Sen GL, Wehrman TS, Blau HM. (2005). mRNA translation is not a prerequisite for small interfering RNA-mediated mRNA cleavage. Differentiation 73(6):287-93.
  8. ^ Kloosterman, WP (2004). "Substrate requirements for let-7 function in the developing zebrafish embryo". Nucleic Acids Res. 32 (21): 6284–91. PMID: 15585662. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  9. ^ Flynt, AS (2007). "Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate". Nature Genetics. 39: 259–263. PMID: 15585662. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ Meister, G (2004). "Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing". RNA. 10 (3): 544–50. PMID: 14970398. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  11. ^ Kloosterman, WP (2006). "In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes". Nat Methods (1): 27–9. PMID: 16369549. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |voluime= ignored (help)
  12. ^ Brown BD, Venneri MA, Zingale A, Sergi LS, Naldini L (2006). "Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer". Nature Medicine. 12 (5): 585–591. PMID 16633348.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005). "A microRNA polycistron as a potential human oncogene". Nature. 435 (7043): 828–833. PMID 15944707.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005). "c-Myc-regulated microRNAs modulate E2F1 expression". Nature. 435 (7043): 839–843. PMID 15944709.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005). "MicroRNA expression profiles classify human cancers". Nature. 435 (7043): 834–838. PMID 15944708.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

  • This paper discusses the role of microRNAs in Host-virus interactions Retrovirology: Scaria V (2006). "Host-Virus Interaction: A new role for microRNAs". Retrovirology. 3 (1): 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. 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. PMID 12242426.
  • This paper describes the discovery of lin-4, the first miRNA to be discovered (editor's note: in fact, no Wikipedia editor has yet read this paper, only made inferences from a citation): 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. PMID 8252621.{{cite journal}}: CS1 maint: multiple names: authors list (link)

See also


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