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===Biomedicine===
===Biomedicine===


Since at least the mid-2000s, there has been intensifying interest in developing short interfering RNAs for biomedical and therapeutic applications.<ref name="Kim 173–184">{{cite journal|last=Kim|first=Daniel H.|coauthors=Rossi, John J.|title=Strategies for silencing human disease using RNA interference|journal=Nature Reviews Genetics|date=1 March 2007|volume=8|issue=3|pages=173–184|doi=10.1038/nrg2006}}</ref> Bolstering this interest is a growing number of experiments which have successfully demonstrated the clinical potential and safety of small RNAs for combatting diseases ranging from viral infections to cancer as well as neurodegenerative disorders.<ref>{{cite journal|last=Stevenson|first=Mario|title=Therapeutic Potential of RNA Interference|journal=New England Journal of Medicine|date=21 October 2004|volume=351|issue=17|pages=1772–1777|doi=10.1056/NEJMra045004}}</ref> As early as 2004, for example, Acuity Pharmaceuticals and Sirna Therapeutics filed [[Investigational New Drug]] ('''IND''') applications with the [[Food and Drug Administration|U.S. Food and Drug Administration]] ('''FDA''') to begin clinical trials on modified [[siRNA]] molecules in order to treat patients with age-related [[macular degeneration]].<ref name="Karagiannis 787–795"/> Today, common methods include the synthesis and delivery of RNA oligonucleotides as well as expressing RNAi triggers from viral vectors, both of which have been successfully developed for inducing RNA silencing in cell culture as well as in vivo.<ref>{{cite journal|last=Davidson|first=Beverly L.|coauthors=McCray, Paul B.|title=Current prospects for RNA interference-based therapies|journal=Nature Reviews Genetics|date=1 May 2011|volume=12|issue=5|pages=329–340|doi=10.1038/nrg2968}}</ref> Optimistically many studies indicate that small RNA-based therapies may offer novel and potent weapons against pathogens and diseases where small molecule/pharmacologic and vaccine/biologic treatments have failed or proved less effective in the past.<ref name="Kim 173–184"/> However, it is also warned that the design and delivery of small RNA effector molecules should be carefully considered in order to ensure safety and efficacy.
Since at least the mid-2000s, there has been intensifying interest in developing short interfering RNAs for biomedical and therapeutic applications.<ref name="Kim 173–184">{{cite journal|last=Kim|first=Daniel H.|coauthors=Rossi, John J.|title=Strategies for silencing human disease using RNA interference|journal=Nature Reviews Genetics|date=1 March 2007|volume=8|issue=3|pages=173–184|doi=10.1038/nrg2006}}</ref> Bolstering this interest is a growing number of experiments which have successfully demonstrated the clinical potential and safety of small RNAs for combatting diseases ranging from viral infections to cancer as well as neurodegenerative disorders.<ref>{{cite journal|last=Stevenson|first=Mario|title=Therapeutic Potential of RNA Interference|journal=New England Journal of Medicine|date=21 October 2004|volume=351|issue=17|pages=1772–1777|doi=10.1056/NEJMra045004}}</ref> As early as 2004, for example, Acuity Pharmaceuticals and Sirna Therapeutics filed [[Investigational New Drug]] ('''IND''') applications with the [[Food and Drug Administration|U.S. Food and Drug Administration]] ('''FDA''') to begin clinical trials on modified [[siRNA]] molecules in order to treat patients with age-related [[macular degeneration]].<ref name="Karagiannis 787–795"/> Today, common methods include the synthesis and delivery of RNA oligonucleotides as well as expressing RNAi triggers from viral vectors, both of which have been successfully developed for inducing RNA silencing in cell culture as well as in vivo.<ref name=Davidson>{{cite journal|last=Davidson|first=Beverly L.|coauthors=McCray, Paul B.|title=Current prospects for RNA interference-based therapies|journal=Nature Reviews Genetics|date=1 May 2011|volume=12|issue=5|pages=329–340|doi=10.1038/nrg2968}}</ref> Optimistically many studies indicate that small RNA-based therapies may offer novel and potent weapons against pathogens and diseases where small molecule/pharmacologic and vaccine/biologic treatments have failed or proved less effective in the past.<ref name="Kim 173–184"/> However, it is also warned that the design and delivery of small RNA effector molecules should be carefully considered in order to ensure safety and efficacy.


===Laboratory===
===Laboratory===

Revision as of 03:40, 10 May 2013

RNA silencing (associated with the concept of post-transcriptional gene silencing (PTGS) or RNA interference) refers to a family of gene silencing effects by which the expression of one or more genes is downregulated or entirely suppressed by the introduction of an antisense RNA molecule. The most common and well-studied example is RNA interference, in which endogenously expressed microRNA or exogenously derived small interfering RNA induces the degradation of complementary messenger RNA.

Background

RNA silencing describes several mechanistically related pathways which are involved in controlling and regulating gene expression.[1][2][3] RNA silencing pathways are associated with the regulatory activity of small non-coding RNAs (approximately 20–30 nucleotides in length) that function as factors involved in inactivating homologous sequences, promoting endonuclease activity, translational arrest, and/or chromatic or DNA modification.[4][5][6] In the context in which the phenomenon was first studied, small RNA was found to play an important role in defending plants against viruses. For example, these studies demonstrated that enzymes detect double-stranded RNA (dsRNA) not normally found in cells and digest it into small pieces that are not able to cause disease.[7][8][9][10][11]

RNA has been largely investigated within its role as an intermediary in the translation of genes into proteins.[12] More active regulatory functions, however, only began to be addressed by researchers beginning in the late-1990s.[13] The landmark study providing an understanding of the first identified mechanism was published in 1998 by Fire et al.,[14] demonstrating that double-stranded RNA could act as a trigger for gene silencing.[13] Since then, various other classes of RNA silencing have been identified and characterized.[1] Presently, the therapeutic potential of these discoveries is being explored, for example, in the context of targeted gene therapy.[15][16]

While RNA silencing is an evolving class of mechanisms, a common theme is the fundamental relationship between small RNAs and gene expression.[5] It has also been observed that the major RNA silencing pathways currently identified have mechanisms of action which may involve both post-transcriptional gene silencing (PTGS)[17] as well as chromatin-dependent gene silencing (CDGS) pathways.[1] CDGS involves the assembly of small RNA complexes on nascent transcripts and is regarded as encompassing mechanisms of action which implicate transcriptional gene silencing (TGS) and co-transcriptional gene silencing (CTGS) events.[18] This is significant at least because the evidence suggests that small RNAs play a role in the modulation of chromatin structure and TGS.[19][20]

Despite early focus in the literature on RNA interference (RNAi) as a core mechanism which occurs at the level of messenger RNA (mRNA) translation, others have since been identified in the broader family of conserved RNA silencing pathways acting at the DNA and chromatin level.[21] RNA silencing refers to the silencing activity of a range of small RNAs and is generally regarded as a broader category than RNAi. While the terms have sometimes been used interchangeably in the literature, RNAi is generally regarded as a branch of RNA silencing. To the extent it is useful to craft a distinction between these related concepts, RNA silencing may be thought of as referring to the broader scheme of small RNA related controls involved in gene expression and the protection of the genome against mobile repetitive DNA sequences, retroelements, and transposons to the extent that these can induce mutations.[22] The molecular mechanisms for RNA silencing were initially studied in plants[9] but have since broadened to cover a variety of subjects, from fungi to mammals, providing strong evidence that these pathways are highly conserved.[23]

At least three primary classes of small RNA have currently been identified, namely: small interfering RNA (siRNA), microRNA (miRNA), and piwi-interacting RNA (piRNA).

small interfering RNA (siRNA)

siRNAs act in the nucleus and the cytoplasm and are involved in RNAi as well as CDGS.[1] siRNAs come from long dsRNA precursors derived from a variety of single-stranded RNA (ssRNA) precursors, such as sense and antisense RNAs. siRNAs also come from hairpin RNAs derived from transcription of inverted repeat regions. siRNAs may also arise enzymatically from non-coding RNA precursors.[24] The volume of literature on siRNA within the framework of RNAi is extensive.

microRNA (miRNA)

The majority of miRNAs act in the cytoplasm and mediate mRNA degradation or translational arrest.[25] However, some plant miRNAs have been shown to act directly to promote DNA methylation.[26] miRNAs come from hairpin precursors generated by the RNaseIII enzymes Drosha and Dicer.[27] Both miRNA and siRNA form either the RNA-induced silencing complex (RISC) or the nuclear form of RISC known as RNA-induced transcriptional silencing complex (RITS).[28] The volume of literature on miRNA within the framework of RNAi is extensive.

piwi-interacting RNA (piRNA)

piRNAs represent the largest class of small non-coding RNA molecules expressed in animal cells, deriving from a large variety of sources, including repetitive DNA and transposons.[29] However, the biogenesis of piRNAs is also the least well understood.[30] piRNAs appear to act both at the post-transcriptional and chromatin levels. They are distinct from miRNA due to at least an increase in terms of size and complexity. Repeat associated small interfering RNA (rasiRNAs) are considered to be a subspecies of piRNA.[31]

Mechanism

MiRNA processing

The most basic mechanistic flow for RNA Silencing is as follows: (For a more detailed explanation of the mechanism, refer to the RNAi:Cellular mechanism article.)

1: RNA with inverted repeats hairpin/panhandle constructs --> 2: dsRNA --> 3: miRNAs/siRNAs --> 4: RISC --> 5: Destruction of target mRNA

  1. It has been discovered that the best precursor to good RNA silencing is to have single stranded antisense RNA with inverted repeats which, in turn, build small hairpin RNA and panhandle constructs.[3] The hairpin or panhandle constructs exist so that the RNA can remain independent and not anneal with other RNA strands.
  2. These small hairpin RNAs and/or panhandles then get transported from the nucleus to the cytosol through the nuclear export receptor called exportin-5, and then get transformed into a dsRNA, a double stranded RNA, which, like DNA, is a double stranded series of nucleotides. If the mechanism didn't use dsRNAs, but only single strands, there would be a higher chance for it to hybridize to other "good" mRNAs. As a double strand, it can be kept on call for when it is needed.
  3. The dsRNA then gets cut up by a Dicer into small (21-28 nt = nucleotides long) strands of miRNAs (microRNAs) or siRNAs (short interfering RNAs.) A Dicer is an endoribonuclease RNase, which is a complex of a protein mixed with strand(s) of RNA.
  4. Lastly, the double stranded miRNAs/siRNAs separate into single strands; the antisense RNA strand of the two will combine with another endoribonuclease enzyme complex called RISC (RNA-induced silencing complex), which includes the catalytic component Argonaute, and will guide the RISC to break up the "perfectly complementary" target mRNA or viral genomic RNA so that it can be destroyed.[11][3]
  5. It means that based on a short sequence specific area, a corresponding mRNA will be cut. To make sure, it will be cut in many other places as well. (If the mechanism only worked with a long stretch, then there would be higher chance that it would not have time to match to its complementary long mRNA.) It has also been shown that the repeated-associated short interference RNAs (rasiRNA) have a role in guiding chromatin modification.[11]

Biological Functions

Immunity against viruses or transposons

RNA silencing is the mechanism that our cells (and cells from all kingdom (biology)) use to fight RNA viruses and transposons (which originate from our own cells as well as from other vehicles.) [11] In the case of RNA viruses, these get destroyed immediately by the mechanism cited above. In the case of transposons, it's a little more indirect. Since transposons are located in different parts of the genome, the different transcriptions from the different promoters produce complementary mRNAs that can hybridize with each other. When this happens, the RNAi machinery goes into action, debilitating the mRNAs of the proteins that would be required to move the transposons themselves.[32]

Down-regulation of genes

For a detailed explanation of the down-regulation of genes, see RNAi:downregulation of genes

Up-regulation of genes

For a detailed explanation of the up-regulation of genes, see RNAi:upregulation of genes

RNA silencing also gets regulated

The same way that RNA silencing regulates downstream target mRNAs, RNA silencing itself is regulated. For example, silencing signals get spread between cells by a group of enzymes called RdRPs (RNA-dependent RNA polymerases) or RDRs.[11]

Applications

Growing understanding of small RNA gene-silencing mechanisms involving dsRNA-mediated sequence-specific mRNA degradation has directly impacted the fields of functional genomics, biomedicine, and experimental biology. The following section describes various applications involving the effects of RNA silencing.

Biotechnology

Artificial introduction of long dsRNAs or siRNAs has been adopted as a tool to inactivate gene expression, both in cultured cells and in living organisms.[11] Structural and functional resolution of small RNAs as the effectors of RNA silencing has had a direct impact on experimental biology. For example, dsRNA may be synthesized to have a specific sequence complementary to a gene of interest. Once introduced into a cell or biological system, it is recognized as exogenous genetic material and activates the corresponding RNA silencing pathway. This mechanism can be used to effect decreases in gene expression with respect to the target, useful for investigating loss of function for genes relative to a phenotype. That is, studying the phenotypic and/or physiologic effects of expression decreases can reveal the role of a gene product. The observable effects can be nuanced, such that some methods can distinguish between “knockdown” (decrease expression) and “knockout” (eliminate expression) of a gene.[33] RNA interference technologies have been noted recently as one of the most widely utilized techniques in functional genomics.[34] Screens developed using small RNAs have been used to identify genes involved in fundamental processes such as cell division, apoptosis and fat regulation.

Biomedicine

Since at least the mid-2000s, there has been intensifying interest in developing short interfering RNAs for biomedical and therapeutic applications.[35] Bolstering this interest is a growing number of experiments which have successfully demonstrated the clinical potential and safety of small RNAs for combatting diseases ranging from viral infections to cancer as well as neurodegenerative disorders.[36] As early as 2004, for example, Acuity Pharmaceuticals and Sirna Therapeutics filed Investigational New Drug (IND) applications with the U.S. Food and Drug Administration (FDA) to begin clinical trials on modified siRNA molecules in order to treat patients with age-related macular degeneration.[34] Today, common methods include the synthesis and delivery of RNA oligonucleotides as well as expressing RNAi triggers from viral vectors, both of which have been successfully developed for inducing RNA silencing in cell culture as well as in vivo.[37] Optimistically many studies indicate that small RNA-based therapies may offer novel and potent weapons against pathogens and diseases where small molecule/pharmacologic and vaccine/biologic treatments have failed or proved less effective in the past.[35] However, it is also warned that the design and delivery of small RNA effector molecules should be carefully considered in order to ensure safety and efficacy.

Laboratory

Research

Recent discoveries

Open ended questions

See also

References

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  16. ^ Dykxhoorn, DM (2003 Jun). "Killing the messenger: short RNAs that silence gene expression". Nature reviews. Molecular cell biology. 4 (6): 457–67. PMID 12778125. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  28. ^ Irvine, DV (2006 Aug 25). "Argonaute slicing is required for heterochromatic silencing and spreading". Science (New York, N.Y.). 313 (5790): 1134–7. PMID 16931764. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ Klattenhoff, C (2008 Jan). "Biogenesis and germline functions of piRNAs". Development (Cambridge, England). 135 (1): 3–9. PMID 18032451. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  30. ^ Ishizu, H (2012 Nov 1). "Biology of PIWI-interacting RNAs: new insights into biogenesis and function inside and outside of germlines". Genes & development. 26 (21): 2361–73. PMID 23124062. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  31. ^ Gunawardane, LS (2007 Mar 16). "A slicer-mediated mechanism for repeat-associated siRNA 5' end formation in Drosophila". Science (New York, N.Y.). 315 (5818): 1587–90. PMID 17322028. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  32. ^ Matthew P Scott; Lodish, Harvey F.; Arnold Berk; Kaiser, Chris; Monty Krieger; Anthony Bretscher; Hidde Ploegh; Angelika Amon (2012). Molecular Cell Biology. San Francisco: W. H. Freeman. ISBN 1-4292-3413-X.{{cite book}}: CS1 maint: multiple names: authors list (link)
  33. ^ Voorhoeve, PM (2003 Jan). "Knockdown stands up". Trends in biotechnology. 21 (1): 2–4. PMID 12480342. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  34. ^ a b Karagiannis, Tom C (13 May 2005). "RNA interference and potential therapeutic applications of short interfering RNAs". Cancer Gene Therapy. 12 (10): 787–795. doi:10.1038/sj.cgt.7700857. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  35. ^ a b Kim, Daniel H. (1 March 2007). "Strategies for silencing human disease using RNA interference". Nature Reviews Genetics. 8 (3): 173–184. doi:10.1038/nrg2006. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  36. ^ Stevenson, Mario (21 October 2004). "Therapeutic Potential of RNA Interference". New England Journal of Medicine. 351 (17): 1772–1777. doi:10.1056/NEJMra045004.
  37. ^ Davidson, Beverly L. (1 May 2011). "Current prospects for RNA interference-based therapies". Nature Reviews Genetics. 12 (5): 329–340. doi:10.1038/nrg2968. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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