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The article should explain which organisms use RNAi. All eukaryotes? Only eukaryotes? AxelBoldt 02:38, 12 February 2006 (UTC)
RNAi is due to a conserved mechanism in nematodes, insects, plants and mammals. These are the organisms I know of, not sure of others. Xanin 19:24, 17 April 2006 (UTC)
Removed Link Directory Spam Bioinformin
I do not like the use of the word "knockout" to describe RNAi in this article:
RNAi is not knockout. I have only ever heard knockout used to describe permanent genetic modification. Knockdown is the term that is used for RNA interference universally. Peter Znamenskiy 19:18, 7 June 2006 (UTC)
You are absolutely correct. Nobody uses the word "knockout" to describe RNAi.
Andrew Fire's paper "RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans" specifically says "knock-out" in the introduction.
this term is not universally used - "knockdown" more accurately describes the process. "Knockout" implies that gene expression has been completely abolished (in RNAi it normally isn't completely). "Knockout" is better suited to describe complete genetic removal of expression normally via transgenics Goldfinger820 03:07, 16 May 2007 (UTC)
I was under the impression that RNAi, antisense RNA and miRNA too are all different things (with overlap of course). -- Rajah 20:47, 27 June 2006 (UTC)
Here's a good reference showing the two are different: [1]. I don't mind if the articles are merged, I just think that it should be pointed out that antisense RNA and RNAi aren't necessarily the same thing. -- Rajah 21:05, 27 June 2006 (UTC)
That is not an appropriate link for this page, and repeatedly restoring it without discussion is inappropriate as well. The link is to a personal advocacy site related to an obscure authorship dispute that is irrelevant to the general discussion of RNAi presented here, and the inclusion of only one disputant's opinion on the matter is a violation of the neutral point of view policy. To the anonymous user who has repeatedly inserted this link, please do not do so again, especially not without discussion. Opabinia regalis 23:48, 21 July 2006 (UTC)
I disagree. I think to call the site an "obscure authorship" dispute is dishonest. The author of "RNA interference page" credits and singles out Craig Mello and Andrew Fire as the discoverers of RNAi by name, and yet when a link is presented to the readers with the possibility that Craig Mello and Andrew Fire may have committed an intellectual fraud and thievery to credit themselves as the conceivers of RNAi (based on their own inconsistent stories of conception; the entire website is dedicated to what led Mello et al and Fire et al to the recognition that the key interfering agent mediating RNAi was/is indeed dsRNA molecule, not about authorship dispute as the editor claims), the readers should be allowed to read upon an alternative and factually disputed assertion detailed in the website. I think, ‘Mr. Editor’ should not deprive his readers of this 'controversy' or at the very least explain why he implicitly portray (by name) Craig Mello and Andy fire as the real co-discoverers of RNAi, if the page were dedicated to a "general" discussion of RNAi. Why leave out the thousands of other equally worthy scientists who ultimately contributed to the discovery of RNAi???? Mention their name too. Let me know if you need help with names. Plus who are you...more relevantly what makes you the self-proclaimed “RNA interference historian” in any case?—Preceding unsigned comment added by Mussaali ( talk • contribs) 20:32, 23 July 2006 mussa ali
Since you are the self styling RNAi historian, I think I am dying to know who you are. Are you friends of Mello and Fire? Have you done any work with RNAi before its conception. I agree with you a key recognition was published by mello and fire in 1998. And since you went to the trouble of highlighting that "historic eureka moment" any 'controvery' surrounding it is a fair game. Don't you think? Otherwise the self proclaimed historians would be having a field day and pushing a personal and biased history down everybody's throat as the true history. mussa ali
"Mello and Fire are the commonly recognized discoverers of RNAi"?? I think you should rephrase that to read as Craig and Andy are commonly extolled for having disclosed a key RNAi finding in their lab. Do you know that Craig Mello had stated publicly that he has “discarded” the original RNAi notebooks. That is a public record and verifiable. I bet in your eyes this is completely irrelevant! I will have more to say....later mussa ali—Preceding unsigned comment added by Mussaali ( talk • contribs)
Enough about the rnaiconception.com website issue…
Let’s look at your loose use of the word “noticed”. Since you weren’t there in either Mello’s or Fire’s lab, you do not have or ever had a first hand knowledge of who may have “noticed” it first. i.e., assuming by “noticed” you mean to infer “recognized” or “conceived.” (If you need a more direct Mello audio back up? Let me know…) mussa ali
More relevantly, (I am generously assuming that you have some RNAi background, and I encourage you to read my perspective on the competing RNAi-induction models), your use of the word “noticed” may be mechanistically flawed. Assuming Fire’s paradigm is correct, that is a dsRNA contaminant (unbeknownst to us at the time) was sufficently inducing RNAi in C. elegans, the first group to have “noticed” or observed dsRNA mediated interference in C. elegans was that of Dr. Kempheus group at Cornell in 1995. (For starters, You should hyperlink Cornell and Dr. Kempheus too). mussa ali
As such I think you should replace the word “noticed” with “reported”. mussa ali
Again you should let your readers know who you really are at least in terms of your scientific credentials and just as relevantly your affiliations(s)…..before you start deleting other people’s website with shameless pomposity. mussa ali—Preceding unsigned comment added by Mussaali ( talk • contribs)
It is time to remind the people posting here to be WP:CIVIL. Personal attacks are never appropriate. Ted Talk/ Contributions 00:10, 25 July 2006 (UTC)
Although I have many issues with the website, I thank you for fixing one of its major flaws. Appreciate it. —Preceding unsigned comment added by Mussaali ( talk • contribs) 21:58, 24 July 2006
By way of closing, and assuming that the editor of this page has no ulterior motive(s) and or is not (or has ever been) C&A's friend and was not engaging in a tacit C&A promotional exercise, I want to apologize for some of the comments I have made. I think I may have gone a bit overboard. I also would like to commend the editor for the significant changes that have been made to the original version of this page, which was the genesis of my contentions.
Mussaali I have removed the conversation on this page that had nothing to do with RNAi. If you feel the need to continue this conversation please continue on Opabinia regalis' talk page. David D. (Talk) 02:51, 30 September 2006 (UTC)
This is a note to ‘Ted’ and ‘O. Regalis’: I have heard it through the grapevine that you guys are unrelentingly impugning me and letting your comments--which in my opinion reads more like a poorly scripted hate speech than a truly scientific analysis of RNAi and how it was discovered--appear prominently when one googles mussa; keep on spewing. O.R: you may have a point when you indicated that I may have not included (at www.rnaiconception.com) what the other side may be saying by way of response; so I will include documents which reflect the other side’s stand: which really is stonewall, stonewall and further stonewall. I have also included a downloadable conception audio link.
At the end of the day, the truth will perdure. Given the convoluted history of RNAi....just remember guys that the Fire-Mello published work is worthy of note because of the key Recognition --and validation of such ---that dsRNA is the key molecule mediating RNAi.
"RNAi is distinct from other gene silencing phenomena in that silencing can spread from cell to cell and generate heritable phenotypes in first generation progeny when used in Caenorhabditis elegans." This sentence is in the introduction. There is nothing relating to this sentence in the main text so we need a section on the systemic nature of RNAi silencing. But first, what are the "other gene silencing phenomena" being referred to here? I assume X-inactivation, imprinting and heterochromatin. Or is it something else? David D. (Talk) 06:17, 26 July 2006 (UTC)
Specifically, Trypanosoma cruzi, in which (I've been told) "post-transcriptional gene silencing" was about as thoroughly charactertized at the time of the Fire/Mello paper as it was in pentunias and worms. Probably deserves mention under Cellular Mechanism and History. Og0709 13:28, 2 October 2006 (UTC)
I have removed the following text that had been recently added by Xuanwu, since it is an inappropriate and subjective editorialization:
"Mello and Fire's research was directly based on the work of a team lead by two Indian scientists, Dr. Utpal Bhadra and Manika Pal Bhadra. Together with a third researcher, Dr. Jim Birchler, they described gene silencing in animals in a Cell article published in 1997, a year before Fire and Mello's landmark paper.[3] According to Dr. Bhadra, "The work of Andrew and Craig is based on the research of my team from University of Missouri." [4]"
The Bhadra et al. 1997 Cell paper makes an interesting demonstration in an animal system (Drosophila) of the phenomenon of cosuppression, as it was known at the time, albeit without providing much mechanistic insight into the process responsible. This phenomenon had previously been observed only in plants and fungi, but although Bhadra et al. showed that it existed in animals, the phenomenon remained puzzling and unexplained.
The real breakthrough in this field was provided by Fire and Mello in their 1998 Nature paper. Working in C. elegans, they made the crucial demonstrations that (1) gene silencing depended on duplex RNA containing sense and antisense strands homologous to the target mRNA; (2) gene silencing mediated by dsRNA was specific and could be used as a general tool for gene silencing; (3) dsRNA-mediated gene silencing appeared to be catalytic, suggesting the existence of an endogenous enzymatic mechanism for this process.
The work of Fire and Mello was performed in an entirely different system from that of Bhadra et al. and was really entirely unrelated, other than the fact that the effect described by Bhadra et al. may have had a similar basis. In fact, the Fire and Mello paper was a direct extension of several earleir papers on RNA-mediated gene silncing from Fire's group. If the Bhadra et al. observations were indeed a manifestation of RNAi, their data suggesting a dependence on polycomb group proteins is curious, since their is no known role for this protein family in RNAi. Ve ri tas 06:31, 5 October 2006 (UTC)Ve ri tas
We should add a paragraph of piRNA and rasiRNA,because it is RNA silencing just a different means. It seems to be germline specific, but it is significant. GetAgrippa 20:19, 7 October 2006 (UTC)
Not a word, in the main text or the reference list? Odd. Tony 17:15, 10 October 2006 (UTC)
Fire and Mello will give their Nobel lectures on December 8. -- JWSchmidt 15:50, 2 December 2006 (UTC)
Can the article's first paragraph be more clear about the definition of RNAi and the relationship between miRNA and RNAi? "RNAi is mediated by the same cellular machinery that processes microRNA, small RNA molecules involved in large-scale gene regulation in the cell." What does "machinery that processes microRNA" mean? Is the intent to make reference to Dicer and the processing of pre-miRNA? Is the intent to make reference to the involvement of the RISC complex in the mRNA-degrading action of a RISC complex nuclease that can be targeted either by siRNA or miRNA?
It seems like there might be two different views about how RNA interference should be defined. According to
this article, "RNA interference (RNAi) is a posttranscriptional gene silencing mechanism in eukaryotes, which can be triggered by small RNA molecules such as microRNA (miRNA) and small interfering RNA (siRNA)." A broad definition of RNA interference would just say that it involves double-stranded RNA, not specifically siRNA.
This other article uses "posttranscriptional silencing" as a general term, and lists RNA interference as one mechanism, saying: "A hallmark of RNAi is the presence of small interfering RNAs". They try to distinguish multiple mechanisms by which microRNA can act in posttranscriptional silencing, only one of which involves RNA-dependent RNA polymerase and the production of siRNA from miRNA. So is RISC complex-mediated mRNA destruction called RNA interference even if siRNA is not involved, but only the double-stranded RNA of pre-miRNA hairpins?
--
JWSchmidt 18:27, 2 December 2006 (UTC)
I just read the Wikipedia article on Dicer, which says, "Dicer is an RNAse III nuclease that cleaves double-stranded RNA (dsRNA) and pre-microRNA (miRNA) into short double-stranded RNA fragments called small interfering RNA (siRNA)". Does Dicer-mediated processing of pre-microRNA result in the production of siRNA or miRNA?
The Wikipedia Dicer article cites
Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ, Adams PD, Doudna JA. (2006). Structural basis for double-stranded RNA processing by Dicer. Science 311(5758):195-8.
Which says, "Dicer first processes input dsRNA into small fragments called short interfering RNAs (siRNAs), or microRNAs (miRNA), which are the hallmark of RNAi." This seems to be another broad definition of RNAi that goes beyond a requirement siRNA.
--
JWSchmidt 03:03, 3 December 2006 (UTC)
The article on microRNA starts out by saying, "Mature miRNA molecules are complementary to regions in one or more messenger RNA (mRNA) molecules, which they target for degradation." Later the article says, "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."
A recent
article in PLoS Biology talks about miRNA-mediated RNA interference and says, "Although RNAi has commonly been associated with siRNAs, this process is largely mediated in plants by miRNAs," and, "miRNAs can behave like siRNAs and induce mRNA cleavage when the miRNA sequence is completely complementary to a target mRNA". However, this paper describes a different miRNA-containing RISC complex that blocks translation by another mechanism: "RCK/p54 is the effector molecule in miRISC that represses translation and that the specificity of this repression is dictated by the sequence of miRNA binding to complementary sites in the 3′ UTR of the target mRNA." (
see their figure 8). They favor a broad definition of RNAi, "RNA interference (RNAi), an evolutionarily conserved process whereby double-stranded RNA induces the sequence-specific degradation of homologous mRNA," and they say, "Endogenously, RNA interference triggers are created from small noncoding RNAs called microRNAs (miRNAs)".
--
JWSchmidt 04:01, 3 December 2006 (UTC)
Recent nature review paper introduce RNA interference like this: "RNA interference (RNAi) is an evolutionarily conserved phenomenon that involves dsRNA molecules. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process." (Nat Rev Mol Cell Biol. 2006 Dec;7(12):919-31.) Sangak 19:17, 3 December 2006 (UTC)
As a biochemist myself, I say we have here a stupendous article, as far as content and writing style are concerned. The only things keeping me from passing it to GA are:
— Parutakupiu talk || contribs 03:14, 1 February 2007 (UTC)
Thumbs up! Great job, you have yourselves another GA. Congratulations! Parutakupiu talk || contribs 18:59, 2 February 2007 (UTC)
This is an area of intense interest and rapid growth. I noted two new RNAi related articles in my Jan. Science: Distinct Populations of Primary and Secondary Effectors During RNAi in C. elegans Julia Pak and Andrew Fire Science 12 January 2007: 241-244.
Secondary siRNAs Result from Unprimed RNA Synthesis and Form a Distinct Class Titia Sijen, Florian A. Steiner, Karen L. Thijssen, and Ronald H. A. Plasterk Science 12 January 2007: 244-247. GetAgrippa 04:28, 1 February 2007 (UTC)
I think that the figure in this article might be a good addition. -- Peta 01:23, 15 February 2007 (UTC)
Hi, the present lead seems kind of daunting for non-experts, since it relies on knowledge that many people won't be familiar with. I at least had a little trouble following it, although maybe that's just me. :( Perhaps we could replace it with something written at a slightly lower level? Here's an initial draft
Please let me know whether you like this version of the lead. Feel free to tinker with it as well. We should wait for Opabinia regalis before doing any substitutions in the main article, though.
Oh, btw, we also might want a reference for the "human disease" sentence. Is it mainly good for viral diseases, or has it been used effectively for bacteria and parasites, too? I haven't looked into it yet.
Hoping that this is useful, Willow 12:03, 15 February 2007 (UTC)
References
{{
cite journal}}
: CS1 maint: multiple names: authors list (
link)
Should there be an article created about it? This article is well researched so I assumed that there was a purpouses on excluding conditional RNA interference. The article touch it from what is implied, but without really covering the subject as it should. Fad (ix) 18:35, 18 February 2007 (UTC)
At first it appears as if this paragraph is about the various applications of RNAi as a tool: to study the function of specific genes, to perform large-scale screens, to study cellular processes, and in biotech and medicine. But then there is one sentence in the middle that doesn't fit the paragraph's general theme: it tells us that the RNAi pathway has been particularly well studied in model organisms. This sentence is about our knowledge of the RNAi pathway, not about its applications. Further, the last sentence uses "also", implying that the last two sentences somehow talk about the same, but they don't.
I propose that the sentence "The RNAi pathway has been particularly well-studied in certain model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the flowering plant Arabidopsis thaliana." be moved from the paragraph about RNAi's applications to a section that describes its discovery and study. AxelBoldt 17:00, 4 March 2007 (UTC)
The figure "Illustration of the major differences between plant and animal gene silencing" misspells "asymmetric". I believe under the image's licence we are OK to modify the spelling in the figure, if anyone wants to have a go. Crana 21:12, 4 May 2007 (UTC)
You're right, it is correct. Weird. I know I wasn't making it up, because the original image [2] has the misspelling. Maybe I looked at the original image and thought I was looking at the WP one? Sorry. Crana 18:36, 5 May 2007 (UTC)
I just uploaded an elegant, simple diagram of RNAi from PLoS to the commons here. Have a look if you're interested. Calliopejen1 16:55, 5 August 2007 (UTC)
In the intro it stated that siRNA only derived from exogeneous sources. This isn't true, it derives from the dsRNA of the same cell, it implies that only humans create siRNA or atleast only other cells create the siRNA that a particular cell requires. I've changed it but i'm not certain if the terminology is correct. All i know is that its more accurate than before. I was surprised to find such an error in the introduction of a featured article to be honest. Perhaps there are other mistakes as I have neither studied this article nor know enough about RNAi to comment. But a check through should definately be required as a featured article suggests that almost everything it contains is correct which doesn't seem to be the case. —Preceding unsigned comment added by 86.133.236.247 ( talk) 12:04, 23 October 2007 (UTC)
I find it astonishing that this article made it to FA with an intro that is extremely difficult for this failed physicist to decipher. It consists of a string of equally indecipherable terms and never explains what is happening inside the cell. If we going to be talking about interference, it's vital that we say what is being interfered with, in terms that don't require lookups in other articles. This needs to be fixed. A link to the gene expression article is simply not good enough, especially considering that that article is in a sorry state. Maury ( talk) 17:42, 21 November 2007 (UTC)
It's slightly better now, but I think it still needs work. To answer David's question, here is one way...
In eukaryotic cells cells, those containing a nucleus, cellular machinery outside of the nucleus produces proteins following instructions stored in the nucleus's genetic material. The overall process is known as gene expression. The instructions for building the proteins are normally communicated through short strands of nucleic acid known as mRNA. mRNA is not the only source of RNA material in the cell, however, viruses and other processes can cause the cellular machinery to produce proteins that are not part of the genetic material, sometimes to the detriment of the organism as a whole.
RNA interference (RNAi) is a mechanism that interferes with the gene expression process in order to control the production of certain proteins. Key to the workings of the RNAi process is small interfering RNA (siRNA), short strands of RNA that have complementary nucleotide sequences to a targeted mRNA strand. The mRNA in question is typically a portion of a longer sequence of long double-stranded RNA (dsRNA), often foreign to the cell. The siRNA "primes" a mechanism within the RNAi pathway that finds the strands of targeted mRNA and "cleaves" then, breaking them down into smaller portions that no longer code properly into a protein. As the RNAi is conserved in most eukaryotic organisms, the pathway may have evolved as a form of innate immunity against viruses and transposons, and also plays a major role in regulating development and genome maintenance.
I believe this clearly states what RNAi does, in context of the overall picture, and does not fall prey to having "no flow whatsoever". YMMV. Maury ( talk) 23:51, 24 November 2007 (UTC)
(undent) That is much better. I would recommend adding in " likely a form of innate immune response" after the word transposon. I am also confused by the last sentence, which is not how I understand it to work. See if this is more accurate:
Maury 22:40, 30 November 2007 (UTC)
I had already changed above, deciding to move the double stranded section to the following paragraph. i think above was a half finished thought on my behalf. I just added back the innate immunity. See the opening two paragraph in the article now. David D. (Talk) 23:10, 30 November 2007 (UTC)
I still find this very difficult. Is this version better?:
"RNA interference (RNAi) is a mechanism that inhibits gene expression by causing the degradation of specific RNA molecules or hindering the transcription of specific genes. RNAi targets include RNA from viruses and transposons (probably as a form of innate immune response), and also plays a role in regulating development and genome maintenance. Small interfering RNA strands (siRNA) are key to the RNAi process, and have complementary nucleotide sequences to the targeted RNA strand. Specific RNAi pathway proteins are guided by the siRNA to the targeted messenger RNA (mRNA), where they "cleave" the target, breaking it down into smaller portions that can no longer be translated into protein. A type of RNA transcribed from the genome itself, microRNA (miRNA), works in the same way." DrKiernan ( talk) 14:57, 11 January 2008 (UTC)
This is a superb, outstanding article, the best on the web. My congratulations to all editor.-- GrahamColm Talk 21:50, 10 February 2008 (UTC)
I don't quite understand how to do the editing nor do I have the time but could someone please add the following ORIGINAL reference to the section for Upregulation of Genes? The current reference is #74. Here is a link to the original paper published on this topic as the current reference is only a review: http://www.pnas.org/cgi/content/abstract/0607015103v1 Thanks Racheloser ( talk) 02:46, 21 February 2008 (UTC)
Did I get it all right? I've been taught it is viral RNA-dependent RNA polymerase that makes dsRNA from a ssRNA and starts RNAi, but the presence of endogenous RdRPs in RNAi makes it a little confusing. Narayanese ( talk) 20:37, 18 March 2008 (UTC)
The article seems to lack any information about the work done on three species of trematode. Donek ( talk) 22:42, 2 November 2008 (UTC)
The "dsRNA cleavage" section confuses me. Paragraph 1 says that dsRNA activates dicer to cleave it, then they are broken into single strands and, finally, the siRNAs are incorporated into RISC. Paragraph 2 seems to start at the beginning again describing how an effector protein detects the dsRNA and then the effector protein stimulates dicer to cleave the dsRNA and that both the effector protein and dicer present the siRNAs to RISC. Have I misunderstood this or is there a problem with the section? Donek ( talk) 16:26, 18 November 2008 (UTC)
What is the difference between RNA silencing and RNA interference. Is it just that RNA silencing is in plants, and RNA interference is in animals, or is there more to it than that? If so, shouldn't the pages be merged? SiameseTurtle ( talk) 19:07, 19 December 2008 (UTC)
In the second paragraph, the term dsRNA is used without prior definition. thanks. —Preceding unsigned comment added by 128.249.96.253 ( talk) 18:32, 23 January 2009 (UTC)
My understanding is that post transcriptional gene silencing (PTGS) originally referred to gene silencing effects in plants. This turned out to be a result of RNA interference and now PTGS rather describes the effects of RNA interference. I think this is already well covered in the lead paragraph and History and discovery sections; so I suggest PTGS should just redirect to RNA interference. Any problems with this? Ribrob ( talk) 16:25, 11 April 2009 (UTC)
RNAi is the same as PTGS, RNA silencing, and Quelling in fungi. I also agree with a merger, but only if this article is developed to include information about the systems in all organisms. This article focusses too much on animal systems. Similarities and differences between the systems need to be highlighted. SiameseTurtle ( talk) 18:56, 11 April 2009 (UTC)
"The relevance of observations from fission yeast mating-type regions and centromeres to mammals is not clear, as heterochromatin maintenance in mammalian cells may be independent of the components of the RNAi pathway.[45]" a paper i have been reading published 2009 suggests that heterochromatin maintenance in yeast might be independent of RNAi as well... is an small update needed?
Alexander Kagansky, Hernan Diego Folco, Ricardo Almeida, Alison L. Pidoux, Abdelhalim Boukaba, Femke Simmer, Takeshi Urano, Georgina L. Hamilton, Robin C. Allshire (2009) Synthetic Heterochromatin Bypasses RNAi and Centromeric Repeats to Establish Functional Centromeres, Science 324, 1716 —Preceding unsigned comment added by X CheshireCat x ( talk • contribs) 16:16, 15 December 2009 (UTC)
PATENTLY, A BATTLE FOR GENETICS' NEXT BIG THING
Who invented hairpin gene silencing? It's literally a $64 million question, as the claimants to one of the most valuable biotechnology patents of the past decade begin skirmishing over its ownership.
Hairpin gene silencing, also known as RNA interference (RNAi), is a simple, quick, but exquisitely precise way of exploring gene function in higher organisms - it can be applied to switching off genes in plants, animals, insects, or any other higher organism. Changes in the organism then provide cues the function of the silenced gene.
There are four contenders: CSIRO Plant Industry, the multinational life science company Syngenta (UK), the Carnegie Institute in the US, and a partnership involving small Queensland-based biotechnology company Benitec Australia and the Queensland Department of Primary Industries (QDPI).
CSIRO lays claim to having discovered hairpin gene silencing in 1994; CSIRO Plant Industry molecular geneticist Dr Peter Waterhouse performed the first successful gene-silencing experiment in a plant - tobacco - in 1995. CSIRO's claim rests on its belief that Waterhouse's experiment was also the first demonstration of this novel method of gene silencing in any organism.
But CSIRO delayed lodging its patent until April 1998; the Benitec/QDPI partnership and Syngenta filed in March 1998. In the intervening period, the Carnegie Institute and Syngenta filed their applications - Carnegie filed on the basis of demonstrating hairpin gene silencing in the nematode Caenorhabditis elegans.
Dr Rob Defeyter, a member of Waterhouse's team, and now IP manager for Plant Industry, said the division prepared a draft patent in 1995, but delayed filing while it conducted further research.
"Our laboratory notebooks confirm we continued our research between 1995 and 1998, mainly to confirm our data, extend the technique, and find out how broadly applicable it might be," Defeyter said.
Benitec's claim is based on work done by former Plant Industry geneticist Dr Mick Graham, who worked with Waterhouse until 1995 before joining QDPI.
Graham was the first to demonstrated successful dsRNA silencing in mammalian cells, and the Benitec/QDPI alliance was the first to file a patent on the technique, in March 1998. The question of ownership is complicated by different views of what constitutes priority. Defeyter said patent offices in most countries, including Australia, based priority on the filing date, but the US Patent Office bases priority on the date of invention - even if the patent application is not lodged until later.
Yesterday CSIRO announced it was releasing the high-throughput gene silencing vectors it has developed for its own work in plants, or free use by any not-for-profit research organisation.
Today, Benitec announced a collaborative agreement with US biotechnology company Tranzyme, in North Carolina, to develop and market its own high- throughput gene-silencing and gene-delivery technologies.
In their joint press release, the companies said the combination of Benitec's High Throughput (HTP) gene silencing technology announced on January 7, 2003, with Tranzyme's industry-proven gene delivery and expression technology, would "offer customers a revolutionary means of producing gene 'knockdowns' quickly and efficiently.
"The combined technologies will be ideal for both in vitro and in vivo applications," it said. "The collaboration will target the pharmaceutical industry and will fast-track the discovery and validation of drug targets." The companies will share revenues, as well as developing their own proprietary targets using the combined technology for future joint commercialisation.
CSIRO's press release yesterday said its gene vectors can be used to identify the function of thousands of genes quickly and accurately, and predicted the technology would promote "major advances in biotechnology and agriculture".
Plant Industry Chief Dr Jim Peacock said, "Scientists can now accurately and rapidly identify the function of single genes or specific groups of genes from tens of thousands of genes in an organism." "As well as the speed of analysis, these vectors provide nearly 100 per cent efficiency in 'switching off' any gene under investigation. This means the effect of a gene in an organism can be determined confidently, and once its function is known we can decide how to use this information." Harbinger of attack Waterhouse's original 1995 experiment confirmed the existence of plant cells of an ancient mechanism, perhaps evolved as a defence against viruses, that detects the presence of double-stranded RNA molecules - a harbinger of viral attack.
When viruses infect living cells, they produce a double-stranded RNA (dsRNA) copy of their genetic blueprints as a prelude to mass-replicating new virus particles.
The anti-viral mechanism detects the dsRNA genetic blueprint, and by an as yet unidentified mechanism, cleaves it into useless fragments, halting the virus replication before it can begin. It is now clear that the cells of higher organisms use the same dsRNA technique to regulate their own gene activity, by producing 'mirror image' messenger RNAs that bind to the active gene's messenger RNA, forming a dsRNA complex - which is then degraded.
The 'knockdown' technique differs from the knockout technique used to silence genes in rodents, in that the DNA code of the original gene is left unaltered - the silencing is performed at the gene-transcription stage.
CSIRO's vectors, which carry names like 'Hannibal', 'Kannibal' and 'Hellsgate' are essentially plug-and-play gene cassettes into which geneticists can insert DNA sequences copied from the many messenger RNAs of active genes in living cells.
The gene sequence, and the complementary DNA code from the non-gene strand, are joined end-to-end, separated by a small sequence that forms a hinge.
When the vector inserts the gene construct into living cells, the transgene produces messenger RNAs that spontaneously fold back on themselves, by complementary base-pairing, forming a hairpin shape.
The resulting dsRNA molecule is then detected by the cell, and destroyed - an event that also programs the anti-viral mechanism to destroy the 'real' mRNAs from the targeted gene.
'The third great revolution' Benitec's director of research and technology, Ken Reed, said yesterday the company was confident of its patent position - "It's a great position to have. Mick Graham was the first, by two and a half years, to demonstrate its efficacy in animal cells.
"It's the third revolution in biotechnology - first there was recombinant DNA technology, then PCR, and now RNA interference," he said "We knew as soon as the world woke up to the fact that it could be used in mammalian cells, there would be the most massive brawl in relation to ownership of the patent.
"In recent years, once companies realized its value, everyone has been trawling back through their research in the early 1990s for anything that might allow them to claim priority. It's bigger than Ben Hur."
Source: http://www.gene.ch/genet/2003/Mar/msg00029.html
Finally, one needs to ask the question as to why, the C.S.I.R.O., the Q.D.P.I. and the Australian company Benitec dominate the RNAi patent landscape if they were simply contributors - remember with the USPTO works on 'first-to-invent' and not 'first-to-file basis.' Undoubtedly, Mello and Fire are great scientists, but the history and discovery section of this article is so narrow in its point of view that a better title might be - 'the life and times of Mello and Fire.'
http://www.pi.csiro.au/RNAi/ HairpinRNAi – a CSIRO invention In 1995, CSIRO was first to recognise the role of double-stranded RNA as the trigger for gene silencing, now popularly known as “RNA Interference” or “RNAi”. When a plant with an antisense construct directed against a virus sequence was crossed with a plant containing a sense construct against the same sequence, only the progeny that acquired both sense and antisense constructs were immune to virus infection (Waterhouse et al., 1998). The key CSIRO invention was a construct with linked sense and antisense or inverted repeat sequences (Figure 1). When transcribed, a self complementary RNA is produced that forms a ‘hairpin’ structure by folding back on itself (Waterhouse et al., 1998). Hairpin RNA with a double-stranded ‘stem’ is a more effective trigger of RNAi than separate sense plus antisense RNAs (Figure 2). This was proved by using constructs containing sequences from a reporter gene (GUS) and a viral gene (Potato Virus Y).
Rodney214 (
talk) 13:30, 20 January 2011 (UTC)
The lead contains:
The text suggests that this applies to all organisms. Is this correct? It appears to be true for plants and Drosophila. I've qualified the statement by adding "In some organisms ..." Aa77zz ( talk) 11:38, 25 November 2011 (UTC)
Especially for the keepers of the history sections: I attended an RNAi symposium in Cambridge in the early 2000s and at least one speaker mentioned that the first RNAi experiment that he was aware of was at Merck in the 1960s(?) or 1970s(?). (The same speaker also mentioned the more well known petunia experiments from the 1990s.) The Merck guys injected RNA into organisms (plants? mice? rats?) and ... I forget what effect they saw. Was anybody else at that symposium besides me? Does anyone have details of the Merck experiment and result? Please excuse the sketchiness of this contribution. AdderUser ( talk) 18:18, 16 September 2014 (UTC)
The comment(s) below were originally left at Talk:RNA interference/Comments, and are posted here for posterity. Following several discussions in past years, these subpages are now deprecated. The comments may be irrelevant or outdated; if so, please feel free to remove this section.
The subject of the 2006 Nobel Prize in Physiology or Medicine - absolutely should be an FA. – Clockwork Soul |
Last edited at 06:48, 3 October 2006 (UTC). Substituted at 03:45, 30 April 2016 (UTC)
First, I am delighted to find out that the article published on one of my most interesting fields is "featured"! In fact, it is truly well structured: clear table of contents and understandable leading overview. I also appreciate the quality of figures and the citation of key references of the main contributions to the RNAi discoveries.
Yet, I would like to point some lacunae: 1. Regarding the figure of the petunias, its reference must be Napoli & Jorgensen (i.e. 162 not 160). And it's important to mention their names in the text. 2. Regarding the first sentence of the article, you saved yourselves by using the diplomatic adverb "typically". Despite this diplomacy, the sentence is still wrong: if the the gene expression (i.e. transcription into mRNA) is inhibited, then there is no more mRNA (upstream) to be destructed. Therefore, to play it safe and cover all possible mechanisms of RNAi, I suggest to rephrase the first sentence as follows: "RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules". This definition covers the possible actions of RNAi: in the nucleus before exit of mRNA to the cytoplasm, cleavage by RISC or blocking the access of ribosomes. 3. I would suggest to add an illustration of the experiment of Mello & Fire, which was central in the RNAi history, instead of simply showing a photo of C. elegans. 4. As for the mechanism of gene silencing, you missed a very crucial step: both miRNA and siRNA have two strands, sense and antisense. So, the major step before destruction by RISC is retaining the antisense and discarding the sense. RLC (RISC-Loading Complex) achieves this selection. 5. Mentioning "Argonaute" as the cleaving protein is braod; let's be more specific: its Argonaute 2 (Ago2)! Then, why was it named argonaute? I'm always interested in knowing and informing the readers about the nomenclatures and etymologies. 6. I would suggest to add some more therapeutic applications of RNAi beside viruses and cancer. By the way, either subtitle "viruses" and "cancers", or "antiviral" and "anti-cancerous", or "virology" and "oncology"! 7. I suggest adding a section about the delivery vehicles of RNAi.
Congratulations again for the quality of the article, especially on the level of organization! I'm available to participate in editing the article upon responses to my present evaluation. Thanks! Oucèma — Preceding unsigned comment added by AboulOus ( talk • contribs) 03:24, 28 October 2016 (UTC)
Hi. A quote from the article: "For instance, in gastrointestinal cancers, nine miRNAs have been identified as epigenetically altered and effective in down regulating DNA repair enzymes." I believe that is an incorrect statement. I believe the correct statement should be: "For instance, in gastrointestinal cancers, nine miRNA genes have been identified as epigenetically altered and thus cause effective down regulation of DNA repair enzymes". Am I mising something? I haven't read the reference and citations from it in excruciating detail, but I don't believe the miRNAs themselves are modified. Small point at the fringe of my knowledge, so I haven't made the change unless I get input. Thanks, DennisPietras ( talk) 13:23, 18 January 2017 (UTC)
@ 2604:2D80:4000:810C:2DF0:7F05:D8D0:9126: Seriously, do you understand the process of translation and how it differs from transcription? If you think you know something that I don't, please explain it here. DennisPietras ( talk) 20:19, 24 January 2017 (UTC)
I think that this page is quite good on RNAi but what concerns me is that "Regulatory RNA" sends me to this page. RNA inhibition using the miRNAs is only one of the presently known kinds of RNA regulator-based systems that regulate gene expression at various levels. miRNAs are usually but not always inhibitory of gene expression, acting post-transcriptionally by activating the degradation of mRNAs that match the miRNA, true.
But there are other kinds of RNA that shut down transcription of blocks of chromatin, for example the Xist and Tsix and related molecules involved in X-inactivation for dosage compensation. Those are long noncoding RNAs (lncRNAs). The chromosome-wide inactivation of genes for transcription occurs via recruiting of polycomb complex. It's an epigenetic regulator of inactive chromatin state.
Enhancer RNAs might turn out to be a subset of the lncRNAs but some of them may be much shorter than the 200bp cutoff; in my view we haven't worked out enough systems regulated by enhancer RNAs to know. But they involve regulation of one or a few genes controlled by the enhancer that is transcribed, not multi-gene blocks of chromatin. I am planning to write an article for Wikipedia briefly summarizing the types of Regulatory RNA. It will connect to this article and the other relevant ones so that the strange cross reference won't have to occur. Please let me know if this sounds counterproductive to you. LLMHoopes ( talk) 10:03, 6 August 2018 (UTC)
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The article should explain which organisms use RNAi. All eukaryotes? Only eukaryotes? AxelBoldt 02:38, 12 February 2006 (UTC)
RNAi is due to a conserved mechanism in nematodes, insects, plants and mammals. These are the organisms I know of, not sure of others. Xanin 19:24, 17 April 2006 (UTC)
Removed Link Directory Spam Bioinformin
I do not like the use of the word "knockout" to describe RNAi in this article:
RNAi is not knockout. I have only ever heard knockout used to describe permanent genetic modification. Knockdown is the term that is used for RNA interference universally. Peter Znamenskiy 19:18, 7 June 2006 (UTC)
You are absolutely correct. Nobody uses the word "knockout" to describe RNAi.
Andrew Fire's paper "RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans" specifically says "knock-out" in the introduction.
this term is not universally used - "knockdown" more accurately describes the process. "Knockout" implies that gene expression has been completely abolished (in RNAi it normally isn't completely). "Knockout" is better suited to describe complete genetic removal of expression normally via transgenics Goldfinger820 03:07, 16 May 2007 (UTC)
I was under the impression that RNAi, antisense RNA and miRNA too are all different things (with overlap of course). -- Rajah 20:47, 27 June 2006 (UTC)
Here's a good reference showing the two are different: [1]. I don't mind if the articles are merged, I just think that it should be pointed out that antisense RNA and RNAi aren't necessarily the same thing. -- Rajah 21:05, 27 June 2006 (UTC)
That is not an appropriate link for this page, and repeatedly restoring it without discussion is inappropriate as well. The link is to a personal advocacy site related to an obscure authorship dispute that is irrelevant to the general discussion of RNAi presented here, and the inclusion of only one disputant's opinion on the matter is a violation of the neutral point of view policy. To the anonymous user who has repeatedly inserted this link, please do not do so again, especially not without discussion. Opabinia regalis 23:48, 21 July 2006 (UTC)
I disagree. I think to call the site an "obscure authorship" dispute is dishonest. The author of "RNA interference page" credits and singles out Craig Mello and Andrew Fire as the discoverers of RNAi by name, and yet when a link is presented to the readers with the possibility that Craig Mello and Andrew Fire may have committed an intellectual fraud and thievery to credit themselves as the conceivers of RNAi (based on their own inconsistent stories of conception; the entire website is dedicated to what led Mello et al and Fire et al to the recognition that the key interfering agent mediating RNAi was/is indeed dsRNA molecule, not about authorship dispute as the editor claims), the readers should be allowed to read upon an alternative and factually disputed assertion detailed in the website. I think, ‘Mr. Editor’ should not deprive his readers of this 'controversy' or at the very least explain why he implicitly portray (by name) Craig Mello and Andy fire as the real co-discoverers of RNAi, if the page were dedicated to a "general" discussion of RNAi. Why leave out the thousands of other equally worthy scientists who ultimately contributed to the discovery of RNAi???? Mention their name too. Let me know if you need help with names. Plus who are you...more relevantly what makes you the self-proclaimed “RNA interference historian” in any case?—Preceding unsigned comment added by Mussaali ( talk • contribs) 20:32, 23 July 2006 mussa ali
Since you are the self styling RNAi historian, I think I am dying to know who you are. Are you friends of Mello and Fire? Have you done any work with RNAi before its conception. I agree with you a key recognition was published by mello and fire in 1998. And since you went to the trouble of highlighting that "historic eureka moment" any 'controvery' surrounding it is a fair game. Don't you think? Otherwise the self proclaimed historians would be having a field day and pushing a personal and biased history down everybody's throat as the true history. mussa ali
"Mello and Fire are the commonly recognized discoverers of RNAi"?? I think you should rephrase that to read as Craig and Andy are commonly extolled for having disclosed a key RNAi finding in their lab. Do you know that Craig Mello had stated publicly that he has “discarded” the original RNAi notebooks. That is a public record and verifiable. I bet in your eyes this is completely irrelevant! I will have more to say....later mussa ali—Preceding unsigned comment added by Mussaali ( talk • contribs)
Enough about the rnaiconception.com website issue…
Let’s look at your loose use of the word “noticed”. Since you weren’t there in either Mello’s or Fire’s lab, you do not have or ever had a first hand knowledge of who may have “noticed” it first. i.e., assuming by “noticed” you mean to infer “recognized” or “conceived.” (If you need a more direct Mello audio back up? Let me know…) mussa ali
More relevantly, (I am generously assuming that you have some RNAi background, and I encourage you to read my perspective on the competing RNAi-induction models), your use of the word “noticed” may be mechanistically flawed. Assuming Fire’s paradigm is correct, that is a dsRNA contaminant (unbeknownst to us at the time) was sufficently inducing RNAi in C. elegans, the first group to have “noticed” or observed dsRNA mediated interference in C. elegans was that of Dr. Kempheus group at Cornell in 1995. (For starters, You should hyperlink Cornell and Dr. Kempheus too). mussa ali
As such I think you should replace the word “noticed” with “reported”. mussa ali
Again you should let your readers know who you really are at least in terms of your scientific credentials and just as relevantly your affiliations(s)…..before you start deleting other people’s website with shameless pomposity. mussa ali—Preceding unsigned comment added by Mussaali ( talk • contribs)
It is time to remind the people posting here to be WP:CIVIL. Personal attacks are never appropriate. Ted Talk/ Contributions 00:10, 25 July 2006 (UTC)
Although I have many issues with the website, I thank you for fixing one of its major flaws. Appreciate it. —Preceding unsigned comment added by Mussaali ( talk • contribs) 21:58, 24 July 2006
By way of closing, and assuming that the editor of this page has no ulterior motive(s) and or is not (or has ever been) C&A's friend and was not engaging in a tacit C&A promotional exercise, I want to apologize for some of the comments I have made. I think I may have gone a bit overboard. I also would like to commend the editor for the significant changes that have been made to the original version of this page, which was the genesis of my contentions.
Mussaali I have removed the conversation on this page that had nothing to do with RNAi. If you feel the need to continue this conversation please continue on Opabinia regalis' talk page. David D. (Talk) 02:51, 30 September 2006 (UTC)
This is a note to ‘Ted’ and ‘O. Regalis’: I have heard it through the grapevine that you guys are unrelentingly impugning me and letting your comments--which in my opinion reads more like a poorly scripted hate speech than a truly scientific analysis of RNAi and how it was discovered--appear prominently when one googles mussa; keep on spewing. O.R: you may have a point when you indicated that I may have not included (at www.rnaiconception.com) what the other side may be saying by way of response; so I will include documents which reflect the other side’s stand: which really is stonewall, stonewall and further stonewall. I have also included a downloadable conception audio link.
At the end of the day, the truth will perdure. Given the convoluted history of RNAi....just remember guys that the Fire-Mello published work is worthy of note because of the key Recognition --and validation of such ---that dsRNA is the key molecule mediating RNAi.
"RNAi is distinct from other gene silencing phenomena in that silencing can spread from cell to cell and generate heritable phenotypes in first generation progeny when used in Caenorhabditis elegans." This sentence is in the introduction. There is nothing relating to this sentence in the main text so we need a section on the systemic nature of RNAi silencing. But first, what are the "other gene silencing phenomena" being referred to here? I assume X-inactivation, imprinting and heterochromatin. Or is it something else? David D. (Talk) 06:17, 26 July 2006 (UTC)
Specifically, Trypanosoma cruzi, in which (I've been told) "post-transcriptional gene silencing" was about as thoroughly charactertized at the time of the Fire/Mello paper as it was in pentunias and worms. Probably deserves mention under Cellular Mechanism and History. Og0709 13:28, 2 October 2006 (UTC)
I have removed the following text that had been recently added by Xuanwu, since it is an inappropriate and subjective editorialization:
"Mello and Fire's research was directly based on the work of a team lead by two Indian scientists, Dr. Utpal Bhadra and Manika Pal Bhadra. Together with a third researcher, Dr. Jim Birchler, they described gene silencing in animals in a Cell article published in 1997, a year before Fire and Mello's landmark paper.[3] According to Dr. Bhadra, "The work of Andrew and Craig is based on the research of my team from University of Missouri." [4]"
The Bhadra et al. 1997 Cell paper makes an interesting demonstration in an animal system (Drosophila) of the phenomenon of cosuppression, as it was known at the time, albeit without providing much mechanistic insight into the process responsible. This phenomenon had previously been observed only in plants and fungi, but although Bhadra et al. showed that it existed in animals, the phenomenon remained puzzling and unexplained.
The real breakthrough in this field was provided by Fire and Mello in their 1998 Nature paper. Working in C. elegans, they made the crucial demonstrations that (1) gene silencing depended on duplex RNA containing sense and antisense strands homologous to the target mRNA; (2) gene silencing mediated by dsRNA was specific and could be used as a general tool for gene silencing; (3) dsRNA-mediated gene silencing appeared to be catalytic, suggesting the existence of an endogenous enzymatic mechanism for this process.
The work of Fire and Mello was performed in an entirely different system from that of Bhadra et al. and was really entirely unrelated, other than the fact that the effect described by Bhadra et al. may have had a similar basis. In fact, the Fire and Mello paper was a direct extension of several earleir papers on RNA-mediated gene silncing from Fire's group. If the Bhadra et al. observations were indeed a manifestation of RNAi, their data suggesting a dependence on polycomb group proteins is curious, since their is no known role for this protein family in RNAi. Ve ri tas 06:31, 5 October 2006 (UTC)Ve ri tas
We should add a paragraph of piRNA and rasiRNA,because it is RNA silencing just a different means. It seems to be germline specific, but it is significant. GetAgrippa 20:19, 7 October 2006 (UTC)
Not a word, in the main text or the reference list? Odd. Tony 17:15, 10 October 2006 (UTC)
Fire and Mello will give their Nobel lectures on December 8. -- JWSchmidt 15:50, 2 December 2006 (UTC)
Can the article's first paragraph be more clear about the definition of RNAi and the relationship between miRNA and RNAi? "RNAi is mediated by the same cellular machinery that processes microRNA, small RNA molecules involved in large-scale gene regulation in the cell." What does "machinery that processes microRNA" mean? Is the intent to make reference to Dicer and the processing of pre-miRNA? Is the intent to make reference to the involvement of the RISC complex in the mRNA-degrading action of a RISC complex nuclease that can be targeted either by siRNA or miRNA?
It seems like there might be two different views about how RNA interference should be defined. According to
this article, "RNA interference (RNAi) is a posttranscriptional gene silencing mechanism in eukaryotes, which can be triggered by small RNA molecules such as microRNA (miRNA) and small interfering RNA (siRNA)." A broad definition of RNA interference would just say that it involves double-stranded RNA, not specifically siRNA.
This other article uses "posttranscriptional silencing" as a general term, and lists RNA interference as one mechanism, saying: "A hallmark of RNAi is the presence of small interfering RNAs". They try to distinguish multiple mechanisms by which microRNA can act in posttranscriptional silencing, only one of which involves RNA-dependent RNA polymerase and the production of siRNA from miRNA. So is RISC complex-mediated mRNA destruction called RNA interference even if siRNA is not involved, but only the double-stranded RNA of pre-miRNA hairpins?
--
JWSchmidt 18:27, 2 December 2006 (UTC)
I just read the Wikipedia article on Dicer, which says, "Dicer is an RNAse III nuclease that cleaves double-stranded RNA (dsRNA) and pre-microRNA (miRNA) into short double-stranded RNA fragments called small interfering RNA (siRNA)". Does Dicer-mediated processing of pre-microRNA result in the production of siRNA or miRNA?
The Wikipedia Dicer article cites
Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ, Adams PD, Doudna JA. (2006). Structural basis for double-stranded RNA processing by Dicer. Science 311(5758):195-8.
Which says, "Dicer first processes input dsRNA into small fragments called short interfering RNAs (siRNAs), or microRNAs (miRNA), which are the hallmark of RNAi." This seems to be another broad definition of RNAi that goes beyond a requirement siRNA.
--
JWSchmidt 03:03, 3 December 2006 (UTC)
The article on microRNA starts out by saying, "Mature miRNA molecules are complementary to regions in one or more messenger RNA (mRNA) molecules, which they target for degradation." Later the article says, "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."
A recent
article in PLoS Biology talks about miRNA-mediated RNA interference and says, "Although RNAi has commonly been associated with siRNAs, this process is largely mediated in plants by miRNAs," and, "miRNAs can behave like siRNAs and induce mRNA cleavage when the miRNA sequence is completely complementary to a target mRNA". However, this paper describes a different miRNA-containing RISC complex that blocks translation by another mechanism: "RCK/p54 is the effector molecule in miRISC that represses translation and that the specificity of this repression is dictated by the sequence of miRNA binding to complementary sites in the 3′ UTR of the target mRNA." (
see their figure 8). They favor a broad definition of RNAi, "RNA interference (RNAi), an evolutionarily conserved process whereby double-stranded RNA induces the sequence-specific degradation of homologous mRNA," and they say, "Endogenously, RNA interference triggers are created from small noncoding RNAs called microRNAs (miRNAs)".
--
JWSchmidt 04:01, 3 December 2006 (UTC)
Recent nature review paper introduce RNA interference like this: "RNA interference (RNAi) is an evolutionarily conserved phenomenon that involves dsRNA molecules. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process." (Nat Rev Mol Cell Biol. 2006 Dec;7(12):919-31.) Sangak 19:17, 3 December 2006 (UTC)
As a biochemist myself, I say we have here a stupendous article, as far as content and writing style are concerned. The only things keeping me from passing it to GA are:
— Parutakupiu talk || contribs 03:14, 1 February 2007 (UTC)
Thumbs up! Great job, you have yourselves another GA. Congratulations! Parutakupiu talk || contribs 18:59, 2 February 2007 (UTC)
This is an area of intense interest and rapid growth. I noted two new RNAi related articles in my Jan. Science: Distinct Populations of Primary and Secondary Effectors During RNAi in C. elegans Julia Pak and Andrew Fire Science 12 January 2007: 241-244.
Secondary siRNAs Result from Unprimed RNA Synthesis and Form a Distinct Class Titia Sijen, Florian A. Steiner, Karen L. Thijssen, and Ronald H. A. Plasterk Science 12 January 2007: 244-247. GetAgrippa 04:28, 1 February 2007 (UTC)
I think that the figure in this article might be a good addition. -- Peta 01:23, 15 February 2007 (UTC)
Hi, the present lead seems kind of daunting for non-experts, since it relies on knowledge that many people won't be familiar with. I at least had a little trouble following it, although maybe that's just me. :( Perhaps we could replace it with something written at a slightly lower level? Here's an initial draft
Please let me know whether you like this version of the lead. Feel free to tinker with it as well. We should wait for Opabinia regalis before doing any substitutions in the main article, though.
Oh, btw, we also might want a reference for the "human disease" sentence. Is it mainly good for viral diseases, or has it been used effectively for bacteria and parasites, too? I haven't looked into it yet.
Hoping that this is useful, Willow 12:03, 15 February 2007 (UTC)
References
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cite journal}}
: CS1 maint: multiple names: authors list (
link)
Should there be an article created about it? This article is well researched so I assumed that there was a purpouses on excluding conditional RNA interference. The article touch it from what is implied, but without really covering the subject as it should. Fad (ix) 18:35, 18 February 2007 (UTC)
At first it appears as if this paragraph is about the various applications of RNAi as a tool: to study the function of specific genes, to perform large-scale screens, to study cellular processes, and in biotech and medicine. But then there is one sentence in the middle that doesn't fit the paragraph's general theme: it tells us that the RNAi pathway has been particularly well studied in model organisms. This sentence is about our knowledge of the RNAi pathway, not about its applications. Further, the last sentence uses "also", implying that the last two sentences somehow talk about the same, but they don't.
I propose that the sentence "The RNAi pathway has been particularly well-studied in certain model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the flowering plant Arabidopsis thaliana." be moved from the paragraph about RNAi's applications to a section that describes its discovery and study. AxelBoldt 17:00, 4 March 2007 (UTC)
The figure "Illustration of the major differences between plant and animal gene silencing" misspells "asymmetric". I believe under the image's licence we are OK to modify the spelling in the figure, if anyone wants to have a go. Crana 21:12, 4 May 2007 (UTC)
You're right, it is correct. Weird. I know I wasn't making it up, because the original image [2] has the misspelling. Maybe I looked at the original image and thought I was looking at the WP one? Sorry. Crana 18:36, 5 May 2007 (UTC)
I just uploaded an elegant, simple diagram of RNAi from PLoS to the commons here. Have a look if you're interested. Calliopejen1 16:55, 5 August 2007 (UTC)
In the intro it stated that siRNA only derived from exogeneous sources. This isn't true, it derives from the dsRNA of the same cell, it implies that only humans create siRNA or atleast only other cells create the siRNA that a particular cell requires. I've changed it but i'm not certain if the terminology is correct. All i know is that its more accurate than before. I was surprised to find such an error in the introduction of a featured article to be honest. Perhaps there are other mistakes as I have neither studied this article nor know enough about RNAi to comment. But a check through should definately be required as a featured article suggests that almost everything it contains is correct which doesn't seem to be the case. —Preceding unsigned comment added by 86.133.236.247 ( talk) 12:04, 23 October 2007 (UTC)
I find it astonishing that this article made it to FA with an intro that is extremely difficult for this failed physicist to decipher. It consists of a string of equally indecipherable terms and never explains what is happening inside the cell. If we going to be talking about interference, it's vital that we say what is being interfered with, in terms that don't require lookups in other articles. This needs to be fixed. A link to the gene expression article is simply not good enough, especially considering that that article is in a sorry state. Maury ( talk) 17:42, 21 November 2007 (UTC)
It's slightly better now, but I think it still needs work. To answer David's question, here is one way...
In eukaryotic cells cells, those containing a nucleus, cellular machinery outside of the nucleus produces proteins following instructions stored in the nucleus's genetic material. The overall process is known as gene expression. The instructions for building the proteins are normally communicated through short strands of nucleic acid known as mRNA. mRNA is not the only source of RNA material in the cell, however, viruses and other processes can cause the cellular machinery to produce proteins that are not part of the genetic material, sometimes to the detriment of the organism as a whole.
RNA interference (RNAi) is a mechanism that interferes with the gene expression process in order to control the production of certain proteins. Key to the workings of the RNAi process is small interfering RNA (siRNA), short strands of RNA that have complementary nucleotide sequences to a targeted mRNA strand. The mRNA in question is typically a portion of a longer sequence of long double-stranded RNA (dsRNA), often foreign to the cell. The siRNA "primes" a mechanism within the RNAi pathway that finds the strands of targeted mRNA and "cleaves" then, breaking them down into smaller portions that no longer code properly into a protein. As the RNAi is conserved in most eukaryotic organisms, the pathway may have evolved as a form of innate immunity against viruses and transposons, and also plays a major role in regulating development and genome maintenance.
I believe this clearly states what RNAi does, in context of the overall picture, and does not fall prey to having "no flow whatsoever". YMMV. Maury ( talk) 23:51, 24 November 2007 (UTC)
(undent) That is much better. I would recommend adding in " likely a form of innate immune response" after the word transposon. I am also confused by the last sentence, which is not how I understand it to work. See if this is more accurate:
Maury 22:40, 30 November 2007 (UTC)
I had already changed above, deciding to move the double stranded section to the following paragraph. i think above was a half finished thought on my behalf. I just added back the innate immunity. See the opening two paragraph in the article now. David D. (Talk) 23:10, 30 November 2007 (UTC)
I still find this very difficult. Is this version better?:
"RNA interference (RNAi) is a mechanism that inhibits gene expression by causing the degradation of specific RNA molecules or hindering the transcription of specific genes. RNAi targets include RNA from viruses and transposons (probably as a form of innate immune response), and also plays a role in regulating development and genome maintenance. Small interfering RNA strands (siRNA) are key to the RNAi process, and have complementary nucleotide sequences to the targeted RNA strand. Specific RNAi pathway proteins are guided by the siRNA to the targeted messenger RNA (mRNA), where they "cleave" the target, breaking it down into smaller portions that can no longer be translated into protein. A type of RNA transcribed from the genome itself, microRNA (miRNA), works in the same way." DrKiernan ( talk) 14:57, 11 January 2008 (UTC)
This is a superb, outstanding article, the best on the web. My congratulations to all editor.-- GrahamColm Talk 21:50, 10 February 2008 (UTC)
I don't quite understand how to do the editing nor do I have the time but could someone please add the following ORIGINAL reference to the section for Upregulation of Genes? The current reference is #74. Here is a link to the original paper published on this topic as the current reference is only a review: http://www.pnas.org/cgi/content/abstract/0607015103v1 Thanks Racheloser ( talk) 02:46, 21 February 2008 (UTC)
Did I get it all right? I've been taught it is viral RNA-dependent RNA polymerase that makes dsRNA from a ssRNA and starts RNAi, but the presence of endogenous RdRPs in RNAi makes it a little confusing. Narayanese ( talk) 20:37, 18 March 2008 (UTC)
The article seems to lack any information about the work done on three species of trematode. Donek ( talk) 22:42, 2 November 2008 (UTC)
The "dsRNA cleavage" section confuses me. Paragraph 1 says that dsRNA activates dicer to cleave it, then they are broken into single strands and, finally, the siRNAs are incorporated into RISC. Paragraph 2 seems to start at the beginning again describing how an effector protein detects the dsRNA and then the effector protein stimulates dicer to cleave the dsRNA and that both the effector protein and dicer present the siRNAs to RISC. Have I misunderstood this or is there a problem with the section? Donek ( talk) 16:26, 18 November 2008 (UTC)
What is the difference between RNA silencing and RNA interference. Is it just that RNA silencing is in plants, and RNA interference is in animals, or is there more to it than that? If so, shouldn't the pages be merged? SiameseTurtle ( talk) 19:07, 19 December 2008 (UTC)
In the second paragraph, the term dsRNA is used without prior definition. thanks. —Preceding unsigned comment added by 128.249.96.253 ( talk) 18:32, 23 January 2009 (UTC)
My understanding is that post transcriptional gene silencing (PTGS) originally referred to gene silencing effects in plants. This turned out to be a result of RNA interference and now PTGS rather describes the effects of RNA interference. I think this is already well covered in the lead paragraph and History and discovery sections; so I suggest PTGS should just redirect to RNA interference. Any problems with this? Ribrob ( talk) 16:25, 11 April 2009 (UTC)
RNAi is the same as PTGS, RNA silencing, and Quelling in fungi. I also agree with a merger, but only if this article is developed to include information about the systems in all organisms. This article focusses too much on animal systems. Similarities and differences between the systems need to be highlighted. SiameseTurtle ( talk) 18:56, 11 April 2009 (UTC)
"The relevance of observations from fission yeast mating-type regions and centromeres to mammals is not clear, as heterochromatin maintenance in mammalian cells may be independent of the components of the RNAi pathway.[45]" a paper i have been reading published 2009 suggests that heterochromatin maintenance in yeast might be independent of RNAi as well... is an small update needed?
Alexander Kagansky, Hernan Diego Folco, Ricardo Almeida, Alison L. Pidoux, Abdelhalim Boukaba, Femke Simmer, Takeshi Urano, Georgina L. Hamilton, Robin C. Allshire (2009) Synthetic Heterochromatin Bypasses RNAi and Centromeric Repeats to Establish Functional Centromeres, Science 324, 1716 —Preceding unsigned comment added by X CheshireCat x ( talk • contribs) 16:16, 15 December 2009 (UTC)
PATENTLY, A BATTLE FOR GENETICS' NEXT BIG THING
Who invented hairpin gene silencing? It's literally a $64 million question, as the claimants to one of the most valuable biotechnology patents of the past decade begin skirmishing over its ownership.
Hairpin gene silencing, also known as RNA interference (RNAi), is a simple, quick, but exquisitely precise way of exploring gene function in higher organisms - it can be applied to switching off genes in plants, animals, insects, or any other higher organism. Changes in the organism then provide cues the function of the silenced gene.
There are four contenders: CSIRO Plant Industry, the multinational life science company Syngenta (UK), the Carnegie Institute in the US, and a partnership involving small Queensland-based biotechnology company Benitec Australia and the Queensland Department of Primary Industries (QDPI).
CSIRO lays claim to having discovered hairpin gene silencing in 1994; CSIRO Plant Industry molecular geneticist Dr Peter Waterhouse performed the first successful gene-silencing experiment in a plant - tobacco - in 1995. CSIRO's claim rests on its belief that Waterhouse's experiment was also the first demonstration of this novel method of gene silencing in any organism.
But CSIRO delayed lodging its patent until April 1998; the Benitec/QDPI partnership and Syngenta filed in March 1998. In the intervening period, the Carnegie Institute and Syngenta filed their applications - Carnegie filed on the basis of demonstrating hairpin gene silencing in the nematode Caenorhabditis elegans.
Dr Rob Defeyter, a member of Waterhouse's team, and now IP manager for Plant Industry, said the division prepared a draft patent in 1995, but delayed filing while it conducted further research.
"Our laboratory notebooks confirm we continued our research between 1995 and 1998, mainly to confirm our data, extend the technique, and find out how broadly applicable it might be," Defeyter said.
Benitec's claim is based on work done by former Plant Industry geneticist Dr Mick Graham, who worked with Waterhouse until 1995 before joining QDPI.
Graham was the first to demonstrated successful dsRNA silencing in mammalian cells, and the Benitec/QDPI alliance was the first to file a patent on the technique, in March 1998. The question of ownership is complicated by different views of what constitutes priority. Defeyter said patent offices in most countries, including Australia, based priority on the filing date, but the US Patent Office bases priority on the date of invention - even if the patent application is not lodged until later.
Yesterday CSIRO announced it was releasing the high-throughput gene silencing vectors it has developed for its own work in plants, or free use by any not-for-profit research organisation.
Today, Benitec announced a collaborative agreement with US biotechnology company Tranzyme, in North Carolina, to develop and market its own high- throughput gene-silencing and gene-delivery technologies.
In their joint press release, the companies said the combination of Benitec's High Throughput (HTP) gene silencing technology announced on January 7, 2003, with Tranzyme's industry-proven gene delivery and expression technology, would "offer customers a revolutionary means of producing gene 'knockdowns' quickly and efficiently.
"The combined technologies will be ideal for both in vitro and in vivo applications," it said. "The collaboration will target the pharmaceutical industry and will fast-track the discovery and validation of drug targets." The companies will share revenues, as well as developing their own proprietary targets using the combined technology for future joint commercialisation.
CSIRO's press release yesterday said its gene vectors can be used to identify the function of thousands of genes quickly and accurately, and predicted the technology would promote "major advances in biotechnology and agriculture".
Plant Industry Chief Dr Jim Peacock said, "Scientists can now accurately and rapidly identify the function of single genes or specific groups of genes from tens of thousands of genes in an organism." "As well as the speed of analysis, these vectors provide nearly 100 per cent efficiency in 'switching off' any gene under investigation. This means the effect of a gene in an organism can be determined confidently, and once its function is known we can decide how to use this information." Harbinger of attack Waterhouse's original 1995 experiment confirmed the existence of plant cells of an ancient mechanism, perhaps evolved as a defence against viruses, that detects the presence of double-stranded RNA molecules - a harbinger of viral attack.
When viruses infect living cells, they produce a double-stranded RNA (dsRNA) copy of their genetic blueprints as a prelude to mass-replicating new virus particles.
The anti-viral mechanism detects the dsRNA genetic blueprint, and by an as yet unidentified mechanism, cleaves it into useless fragments, halting the virus replication before it can begin. It is now clear that the cells of higher organisms use the same dsRNA technique to regulate their own gene activity, by producing 'mirror image' messenger RNAs that bind to the active gene's messenger RNA, forming a dsRNA complex - which is then degraded.
The 'knockdown' technique differs from the knockout technique used to silence genes in rodents, in that the DNA code of the original gene is left unaltered - the silencing is performed at the gene-transcription stage.
CSIRO's vectors, which carry names like 'Hannibal', 'Kannibal' and 'Hellsgate' are essentially plug-and-play gene cassettes into which geneticists can insert DNA sequences copied from the many messenger RNAs of active genes in living cells.
The gene sequence, and the complementary DNA code from the non-gene strand, are joined end-to-end, separated by a small sequence that forms a hinge.
When the vector inserts the gene construct into living cells, the transgene produces messenger RNAs that spontaneously fold back on themselves, by complementary base-pairing, forming a hairpin shape.
The resulting dsRNA molecule is then detected by the cell, and destroyed - an event that also programs the anti-viral mechanism to destroy the 'real' mRNAs from the targeted gene.
'The third great revolution' Benitec's director of research and technology, Ken Reed, said yesterday the company was confident of its patent position - "It's a great position to have. Mick Graham was the first, by two and a half years, to demonstrate its efficacy in animal cells.
"It's the third revolution in biotechnology - first there was recombinant DNA technology, then PCR, and now RNA interference," he said "We knew as soon as the world woke up to the fact that it could be used in mammalian cells, there would be the most massive brawl in relation to ownership of the patent.
"In recent years, once companies realized its value, everyone has been trawling back through their research in the early 1990s for anything that might allow them to claim priority. It's bigger than Ben Hur."
Source: http://www.gene.ch/genet/2003/Mar/msg00029.html
Finally, one needs to ask the question as to why, the C.S.I.R.O., the Q.D.P.I. and the Australian company Benitec dominate the RNAi patent landscape if they were simply contributors - remember with the USPTO works on 'first-to-invent' and not 'first-to-file basis.' Undoubtedly, Mello and Fire are great scientists, but the history and discovery section of this article is so narrow in its point of view that a better title might be - 'the life and times of Mello and Fire.'
http://www.pi.csiro.au/RNAi/ HairpinRNAi – a CSIRO invention In 1995, CSIRO was first to recognise the role of double-stranded RNA as the trigger for gene silencing, now popularly known as “RNA Interference” or “RNAi”. When a plant with an antisense construct directed against a virus sequence was crossed with a plant containing a sense construct against the same sequence, only the progeny that acquired both sense and antisense constructs were immune to virus infection (Waterhouse et al., 1998). The key CSIRO invention was a construct with linked sense and antisense or inverted repeat sequences (Figure 1). When transcribed, a self complementary RNA is produced that forms a ‘hairpin’ structure by folding back on itself (Waterhouse et al., 1998). Hairpin RNA with a double-stranded ‘stem’ is a more effective trigger of RNAi than separate sense plus antisense RNAs (Figure 2). This was proved by using constructs containing sequences from a reporter gene (GUS) and a viral gene (Potato Virus Y).
Rodney214 (
talk) 13:30, 20 January 2011 (UTC)
The lead contains:
The text suggests that this applies to all organisms. Is this correct? It appears to be true for plants and Drosophila. I've qualified the statement by adding "In some organisms ..." Aa77zz ( talk) 11:38, 25 November 2011 (UTC)
Especially for the keepers of the history sections: I attended an RNAi symposium in Cambridge in the early 2000s and at least one speaker mentioned that the first RNAi experiment that he was aware of was at Merck in the 1960s(?) or 1970s(?). (The same speaker also mentioned the more well known petunia experiments from the 1990s.) The Merck guys injected RNA into organisms (plants? mice? rats?) and ... I forget what effect they saw. Was anybody else at that symposium besides me? Does anyone have details of the Merck experiment and result? Please excuse the sketchiness of this contribution. AdderUser ( talk) 18:18, 16 September 2014 (UTC)
The comment(s) below were originally left at Talk:RNA interference/Comments, and are posted here for posterity. Following several discussions in past years, these subpages are now deprecated. The comments may be irrelevant or outdated; if so, please feel free to remove this section.
The subject of the 2006 Nobel Prize in Physiology or Medicine - absolutely should be an FA. – Clockwork Soul |
Last edited at 06:48, 3 October 2006 (UTC). Substituted at 03:45, 30 April 2016 (UTC)
First, I am delighted to find out that the article published on one of my most interesting fields is "featured"! In fact, it is truly well structured: clear table of contents and understandable leading overview. I also appreciate the quality of figures and the citation of key references of the main contributions to the RNAi discoveries.
Yet, I would like to point some lacunae: 1. Regarding the figure of the petunias, its reference must be Napoli & Jorgensen (i.e. 162 not 160). And it's important to mention their names in the text. 2. Regarding the first sentence of the article, you saved yourselves by using the diplomatic adverb "typically". Despite this diplomacy, the sentence is still wrong: if the the gene expression (i.e. transcription into mRNA) is inhibited, then there is no more mRNA (upstream) to be destructed. Therefore, to play it safe and cover all possible mechanisms of RNAi, I suggest to rephrase the first sentence as follows: "RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules". This definition covers the possible actions of RNAi: in the nucleus before exit of mRNA to the cytoplasm, cleavage by RISC or blocking the access of ribosomes. 3. I would suggest to add an illustration of the experiment of Mello & Fire, which was central in the RNAi history, instead of simply showing a photo of C. elegans. 4. As for the mechanism of gene silencing, you missed a very crucial step: both miRNA and siRNA have two strands, sense and antisense. So, the major step before destruction by RISC is retaining the antisense and discarding the sense. RLC (RISC-Loading Complex) achieves this selection. 5. Mentioning "Argonaute" as the cleaving protein is braod; let's be more specific: its Argonaute 2 (Ago2)! Then, why was it named argonaute? I'm always interested in knowing and informing the readers about the nomenclatures and etymologies. 6. I would suggest to add some more therapeutic applications of RNAi beside viruses and cancer. By the way, either subtitle "viruses" and "cancers", or "antiviral" and "anti-cancerous", or "virology" and "oncology"! 7. I suggest adding a section about the delivery vehicles of RNAi.
Congratulations again for the quality of the article, especially on the level of organization! I'm available to participate in editing the article upon responses to my present evaluation. Thanks! Oucèma — Preceding unsigned comment added by AboulOus ( talk • contribs) 03:24, 28 October 2016 (UTC)
Hi. A quote from the article: "For instance, in gastrointestinal cancers, nine miRNAs have been identified as epigenetically altered and effective in down regulating DNA repair enzymes." I believe that is an incorrect statement. I believe the correct statement should be: "For instance, in gastrointestinal cancers, nine miRNA genes have been identified as epigenetically altered and thus cause effective down regulation of DNA repair enzymes". Am I mising something? I haven't read the reference and citations from it in excruciating detail, but I don't believe the miRNAs themselves are modified. Small point at the fringe of my knowledge, so I haven't made the change unless I get input. Thanks, DennisPietras ( talk) 13:23, 18 January 2017 (UTC)
@ 2604:2D80:4000:810C:2DF0:7F05:D8D0:9126: Seriously, do you understand the process of translation and how it differs from transcription? If you think you know something that I don't, please explain it here. DennisPietras ( talk) 20:19, 24 January 2017 (UTC)
I think that this page is quite good on RNAi but what concerns me is that "Regulatory RNA" sends me to this page. RNA inhibition using the miRNAs is only one of the presently known kinds of RNA regulator-based systems that regulate gene expression at various levels. miRNAs are usually but not always inhibitory of gene expression, acting post-transcriptionally by activating the degradation of mRNAs that match the miRNA, true.
But there are other kinds of RNA that shut down transcription of blocks of chromatin, for example the Xist and Tsix and related molecules involved in X-inactivation for dosage compensation. Those are long noncoding RNAs (lncRNAs). The chromosome-wide inactivation of genes for transcription occurs via recruiting of polycomb complex. It's an epigenetic regulator of inactive chromatin state.
Enhancer RNAs might turn out to be a subset of the lncRNAs but some of them may be much shorter than the 200bp cutoff; in my view we haven't worked out enough systems regulated by enhancer RNAs to know. But they involve regulation of one or a few genes controlled by the enhancer that is transcribed, not multi-gene blocks of chromatin. I am planning to write an article for Wikipedia briefly summarizing the types of Regulatory RNA. It will connect to this article and the other relevant ones so that the strange cross reference won't have to occur. Please let me know if this sounds counterproductive to you. LLMHoopes ( talk) 10:03, 6 August 2018 (UTC)