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        【共享】Nature上一篇非常精彩的RNAI的综述

        丁香园论坛

        3883
        最近要写一篇关于RNAi的综述,昨天在nature上面找了一篇关于rnai全文的综述,觉得写的挺好,拿出来分享

        Nature
        (C) 2004 Nature Publishing Group

        ----------------------------------------------
        Volume 431(7006) 16 September 2004 pp 338-342
        ----------------------------------------------

        Revealing the world of RNA interference
        [Insight: Introduction]
        Mello, Craig C.1,2; Conte, Darryl Jr1
        1Howard Hughes Medical Institute and 2Program in Molecular Medicine, University
        of Massachusetts Medical School, Worcester, Massachusetts 01605, USA (e-mail:
        craig.mello@umassmed.edu)

        ----------------------------------------------

        Outline

        Abstract
        Discovering the trigger
        Taking the biological world by storm
        Other silencing triggers
        Outlook for the RNA world

        Acknowledgements
        Competing interests statement

        Graphics

        Figure 1
        Figure 2

        ----------------------------------------------

        Abstract

        The recent discoveries of RNA interference and related RNA silencing pathways
        have revolutionized our understanding of gene regulation. RNA interference has
        been used as a research tool to control the expression of specific genes in
        numerous experimental organisms and has potential as a therapeutic strategy to
        reduce the expression of problem genes. At the heart of RNA interference lies a
        remarkable RNA processing mechanism that is now known to underlie many distinct
        biological phenomena.

        ----------------------------------------------

        The term 'RNA world' was first coined to describe a hypothetical stage in the
        evolution of life some four billion years ago when RNA may have been the genetic
        material and catalyst for emerging life on Earth 1,2. This original RNA world,
        if it ever existed on Earth, is long gone. But this Insight deals with a process
        that reflects an RNA world that is alive and thriving within our cells - RNA
        silencing or RNA interference (RNAi). When exposed to foreign genetic material
        (RNA or DNA), many organisms mount highly specific counter attacks to silence
        the invading nucleic-acid sequences before these sequences can integrate into
        the host genome or subvert cellular processes. At the heart of these sequence-directed
        immunity mechanisms is double-stranded RNA (dsRNA). Interestingly, dsRNA does
        more than help to defend cells against foreign nucleic acids - it also guides
        endogenous developmental gene regulation, and can even control the modification
        of cellular DNA and associated chromatin. In some organisms, RNAi signals are
        transmitted horizontally between cells and, in certain cases, vertically through
        the germ line from one generation to the next. The reviews in this Insight show
        our progress in understanding the mechanisms that underlie RNA-mediated gene
        regulation in plants and animals, and detail current efforts to harness this
        mechanism as a research tool and potential therapy. Here we introduce the world
        of RNAi, and provide a brief overview of this rapidly growing field.

        Discovering the trigger

        Crucial to understanding a gene-silencing mechanism such as RNAi is knowing how
        to trigger it. This is important from the theoretical perspective of understanding
        a remarkable biological response (see review in this issue by Meister and
        Tuschl, page 343); but it also has obvious practical ramifications for using the
        silencing mechanism as an experimental tool (see review in this issue by Hannon
        and Rossi, page 371). The observation by Fire et al.3 that dsRNA is a potent
        trigger for RNAi in the nematode Caenorhabditis elegans (Fig. 1) was important
        because it immediately suggested a simple approach for efficient induction of
        gene silencing in C. elegans and other organisms, and accelerated the discovery
        of a unifying mechanism that underlies a host of cellular and developmental
        pathways. However, there were substantial barriers to the acceptance of the idea
        that dsRNA could trigger sequence-specific gene silencing.

        ----------------------------------------------
        Figure 1 RNAi in C. elegans. Silencing of a green fluorescent protein (GFP)
        reporter in C. elegans occurs when animals feed on bacteria expressing GFP dsRNA
        (a) but not in animals that are defective for RNAi (b). Note that silencing
        occurs throughout the body of the animal, with the exception of a few cells in
        the tail that express some residual GFP. The signal is lost in intestinal cells
        near the tail (arrowhead) as well as near the head (arrow). The lack of
        GFP-positive embryos in a (bracketed region) demonstrates the systemic spread
        and inheritance of silencing.
        ----------------------------------------------

        First, at the time, dsRNA was thought to be a nonspecific silencing agent that
        triggers a general destruction of messenger RNAs and the complete suppression of
        protein translation in mammalian cells 4,5. Second, dsRNA is energetically
        stable and inherently incapable of further specific Watson-Crick base pairing.
        So a model in which dsRNA activates sequence-specific silencing implies the
        existence of cellular mechanisms for unwinding the dsRNA and promoting the
        search for complementary base-pairing partners among the vast pool of cellular
        nucleic-acid sequences. Hypotheses that require a paradigm shift and depend on
        the existence of a whole set of hitherto unknown activities are rarely
        appealing.

        So why was dsRNA proposed as a trigger for RNAi and why was this idea so rapidly
        accepted? To answer this question we must make a brief historical digression. In
        1995, Guo and Kemphues 6 attempted to use RNA complementary to the C. elegans
        par-1 mRNA to block par-1 expression. This technique is known as 'antisense-mediated
        silencing', whereby large amounts of a nucleic acid whose sequence is complementary
        to the target messenger RNA are delivered into the cytoplasm of a cell. Base
        pairing between the 'sense' mRNA sequence and the complementary 'antisense'
        interfering nucleic acid is thought to passively block the processing or
        translation of mRNA, or result in the recruitment of nucleases that promote mRNA
        destruction 7,8. To their surprise, Guo and Kemphues found that both the
        antisense and the control sense RNA preparations induced silencing. Sense RNA is
        identical to the mRNA and so cannot base pair with the mRNA to cause interference,
        raising the question of how this RNA could induce silencing. Was an active
        silencing response being triggered against the foreign RNA, regardless of its
        polarity? Or was the silencing apparently induced by sense RNA actually mediated
        by antisense RNA? (Antisense RNA was known to contaminate the type of in vitro
        transcription products used in these assays.) Despite confusion about the nature
        of the RNA that triggered the phenomenon, this so-called antisense-mediated
        silencing method continued to be used to silence genes in C. elegans.

        More surprises were in store. While using this antisense technique to silence C.
        elegans genes, we were amazed to find that the silencing effect could be
        transmitted in the germ line 3. A remarkably potent silencing signal could be
        passed through the sperm or the egg for up to several generations 3,9. Equally
        remarkable, the silencing effect could also spread from tissue to tissue within
        the injected animal 3. Taken together, the apparent lack of strand specificity,
        the remarkable potency of the RNA trigger, and the systemic spread and
        inheritance properties of the silencing phenomenon prompted the creation of a
        new term, RNAi 10. Importantly, the properties of RNAi demanded the existence of
        cellular mechanisms that initiate and amplify the silencing signal, and led us
        to suggest that the RNAi mechanism represents an active organismal response to
        foreign RNA 3.

        Although our initial models saw dsRNA as an intermediate in the amplification of
        the silencing signal, Fire 3 suggested that dsRNA, which is often encountered by
        cells during viral infection, might itself be the initial trigger. In this
        model, instead of antisense RNA passively initiating silencing by pairing with
        the target mRNA, the presence of low concentrations of both sense and antisense
        strands in the RNA preparation was proposed to result in small amounts of dsRNA:
        on introduction into the animal, this dsRNA could be recognized as foreign,
        thereby activating cellular amplification and inheritance mechanisms. Because it
        was possible to produce and purify in vitro synthesized RNA and introduce it
        directly into C. elegans without the need for transgene-driven expression, this
        theory was easily tested. dsRNA proved to be an extremely potent activator of
        RNAi - at least 10-fold and perhaps 100-fold more effective than purified
        preparations of single-stranded RNA 3.

        Taking the biological world by storm

        With the discovery of an extremely potent trigger for RNAi, it became possible
        to expose large populations of animals to dsRNA: animals were soaked in dsRNA 11
        or given food containing bacterially expressed dsRNA 12,13. By facilitating
        genetic screens, these methods led to the identification of many C. elegans
        genes required for RNAi 14. Comparison of the C. elegans genes required for RNAi
        to genes required for gene silencing in Drosophila15,16, plants 17 and fungi 18
        confirmed that the silencing phenomena known variously as post-transcriptional
        gene silencing (PTGS)19, co-suppression 20, quelling 21 and RNAi, share a common
        underlying mechanism that reflects an ancient origin in a common ancestor of
        fungi, plants and animals. This realization was followed by a flurry of exciting
        results: dsRNA was shown to induce silencing in Drosophila22, and in a host of
        other organisms including organisms that were otherwise unsuited to genetic
        analysis 23,24. Small RNAs were shown to be produced in plants undergoing PTGS
        25, and were identified as the common currency of RNA silencing pathways 26-28
        (see review in this issue by Baulcombe, page 356). The dsRNA-processing enzyme
        Dicer 29 was found to produce these small RNAs, now called short interfering
        RNAs (siRNAs). Synthetic RNAs engineered to look like the products of Dicer were
        shown to induce sequence-specific gene silencing in human cells without
        initiating the nonspecific gene silencing pathways 30. A class of natural
        hairpin dsRNAs 31,32, now called microRNAs (miRNAs; see review in this issue by
        Ambros, page 350), was shown to be processed by Dicer 33-35 and to function
        together with RDE-1 homologues 35, thereby linking the RNAi machinery to a
        natural developmental gene regulatory mechanism. Finally, more recently, the
        RNAi machinery was linked to chromatin regulation in yeast 36, and to chromosomal
        rearrangement during development of the somatic macronucleus in Tetrahymena37.
        These and other breakthroughs united previously disparate fields by identifying
        a common core mechanism that involves the processing of dsRNA into small
        RNA-silencing guides (Fig. 2). In short, dsRNA had taken the biological world by
        storm.

        ----------------------------------------------
        Figure 2 Model depicting distinct roles for dsRNA in a network of interacting
        silencing pathways. In some cases dsRNA functions as the initial stimulus (or
        trigger), for example when foreign dsRNA is introduced experimentally. In other
        cases dsRNA acts as an intermediate, for example when 'aberrant' mRNAs are
        copied by cellular RdRP. Transcription can produce dsRNA by readthrough from
        adjacent transcripts, as may occur for repetitive gene families or high-copy
        arrays (blue dashed arrows). Alternatively, transcription may be triggered
        experimentally or developmentally, for example in the expression of short
        hairpin (shRNA) genes and endogenous hairpin (miRNA) genes. The small RNA
        products of the Dicer-mediated dsRNA processing reaction guide distinct protein
        complexes to their targets. These silencing complexes include the RNA-induced
        silencing complex (RISC), which is implicated in mRNA destruction and translational
        repression, and the RNA-induced transcriptional silencing complex (RITS), which
        is implicated in chromatin silencing. Sequence mismatches between a miRNA and
        its target mRNA lead to translational repression (black solid arrow), whereas
        near perfect complementarity results in mRNA destruction (black dashed arrow).
        Feedback cycles permit an amplification and longterm maintenance of silencing.
        CH3, modified DNA or chromatin; 7mG, 7-methylguanine; AAAA, poly-adenosine tail;
        TGA, translation termination codon.
        ----------------------------------------------

        Other silencing triggers

        Although it was clear that dsRNA was important either as a silencing trigger or
        as an intermediate in all the RNAi-related silencing pathways, it was not known
        whether other stimuli (besides dsRNA) could trigger silencing. For example,
        silencing in response to a DNA transgene could still involve a dsRNA trigger:
        the transgene might integrate itself into the genome in such a way that a nearby
        promoter, or an inverted copy of the transgene itself, leads to the production
        of dsRNA, which could in turn enter directly into the RNAi pathway. Consistent
        with this idea, transgenes engineered to express both sense and antisense
        strands of a gene in plants can lead to efficient silencing, which is more
        reproducible and robust than that achieved by transgenes expressing either
        strand alone 38.

        But several lines of evidence suggest that transgenes can trigger silencing
        through mechanisms not involving a dsRNA trigger (Fig. 2). A key gene family
        involved in silencing pathways in plants 39,40, fungi 41 and C. elegans42,43
        contains genes that encode putative cellular RNA-dependent RNA polymerases
        (RdRPs; also known as RDRs). Members of this family of proteins were identified
        in forward genetic screens - whereby mutant genes are isolated from an organism
        showing abnormal phenotypic characteristics - as factors required for co-suppression
        in plants and quelling in Neurospora. (Co-suppression results from post-transcriptional
        silencing of both a transgene and the endogenous copies of the corresponding
        cellular gene.) Interestingly, although cellular RdRP genes were required for
        transgene-mediated co-suppression in plants 39,40, they were not essential for
        virus-induced silencing of a transgene 39, presumably because the virus provides
        its own viral RNA polymerase. Furthermore, RdRPs have been shown to direct
        primer-independent synthesis of complementary RNA 44,45. Together, these
        findings suggest that the transgene or its single-stranded mRNA products could
        be the original stimulus for co-suppression and quelling. In this type of
        silencing, the RdRP somehow recognizes transgene products as abnormal or
        'aberrant' and subsequently converts this initial silencing trigger into dsRNA
        46,47. In this case, the dsRNA is an intermediate in the silencing pathway
        rather than the trigger. The RdRP-derived dsRNA is then likely to be processed
        by Dicer and to enter downstream silencing complexes that are similar, or
        identical, to those formed in response to a dsRNA trigger.

        But how might the transgene mRNA be recognized as foreign? The answer to this
        question is not known. Hence, this 'aberrant transcript' model has, perhaps
        undeservedly, received little attention of late. One possibility discussed by
        Baulcombe (review in this issue, page 356) is that high levels of expression of
        the transgene mRNA leads to the accumulation of mRNA-processing defects (for
        example, non-polyadenylated transcripts) that are somehow recognized by the
        RdRP. Alternatively, the transgene DNA or the chromatin itself may be 'marked'
        for silencing by the cell. When initially delivered to cells, the transgene DNA
        could be recognized as foreign owing to its lack of associated proteins. During
        the rapid assembly of naked DNA into chromatin 48, the host cell may, in
        self-defence, somehow mark the transgene chromatin so that RdRP is recruited.
        RdRP acting on nascent transcripts could then result in dsRNA formation and
        subsequent silencing. Consistent with this possibility, fission yeast RdRP was
        found to physically associate with silent heterochromatin 36. Despite the
        mysterious nature of the silencing mark recognized by RdRPs, it seems likely
        that, at least in some cases, RdRPs may produce dsRNA that functions as an
        intermediate rather than as the primary trigger for silencing.

        Genetic studies suggest that distinct silencing triggers may also exist in C.
        elegans. Both RDE-1 and the dsRNA-binding protein RDE-4 (ref. 49) are essential
        for mediating the silencing induced by injecting, feeding or expressing dsRNA
        14. However, RDE-1 and RDE-4 are not required for transposon silencing or for
        co-suppression 14,50,51. Furthermore, RDE-1 and RDE-4 are not required for the
        inheritance of RNAi-induced silencing 9, which suggests that they are only
        required during the initial exposure to dsRNA. These findings indicate that
        transposon silencing and co-suppression in C. elegans are initiated by means of
        distinct triggers. As discussed above, an appealing idea is that a chromatin
        'signature' stimulates the production of aberrant transcripts and the formation
        of a novel species of dsRNA (perhaps nuclear) that is distinct from the dsRNA
        that initiates silencing by means of RDE-1 and RDE-4. Again, in this model the
        initial trigger is the chromatin structure of the transposon locus or the
        transgene, and dsRNA acts as an intermediate in the silencing pathway (Fig. 2).
        Perhaps a similar RdRP-derived dsRNA functions in the RDE-1- and RDE-4-independent
        mechanisms that propagate silencing from one generation to the next.

        Ten years ago, de novo cytosine methylation of genomic DNA was shown to occur in
        plants infected with RNA viroids whose sequences were homologous to the
        methylated genomic sequences 52. This process was referred to as RNA-directed
        DNA methylation (RdDM). Subsequently, dsRNA targeting a promoter was shown to
        trigger RdDM and initiate transcriptional silencing. The silencing was
        accompanied by the production of siRNAs 53, pointing to an RNAi-like mechanism
        for the initiation of transcriptional gene silencing. Recent work in fission
        yeast has now convincingly demonstrated that the formation of silent heterochromatin
        can be guided by small RNAs 54 and the RNA-silencing machinery 36. In Drosophila,
        the RNA-silencing machinery was also required for heterochromatin formation and
        for silencing multicopy transgenes and pericentric DNA 55. The discovery of an
        underlying molecular connection between RNA guides and chromatin remodelling has
        been one of the most exciting recent developments in the field of epigenetics.
        It is becoming clear that RNAi has an important role in the initiation of
        heterochromatin formation and transcriptional silencing in plants, fungi and
        animals (see review in this issue by Lippman and Martienssen, page 364).

        The possibility of feedback between RNAi, its potential chromatin-associated
        trigger, and chromatin-mediated silencing maintenance mechanisms raises further
        questions about the ultimate causes of silencing. For example, were C. elegans
        transposons originally silenced by means of an RDE-1/RDE-4-dependent dsRNA
        signal, resulting from sense and antisense readthrough transcription from
        insertion points in the genome 56,57? Perhaps over time this initial dsRNA-triggered
        silencing signal was replaced and augmented by a chromatin-associated silencing-maintenance
        signal.

        Outlook for the RNA world

        The numerous branching and converging silencing pathways that seem to exist in
        diverse organisms will no doubt require many years of research to unravel. It is
        already clear that different organisms have evolved distinct mechanisms, or at
        least variations on a common theme. In some cases, differences seem to exist in
        the extent to which silencing relies on a particular mode of regulation. For
        example, plants show a preponderance of miRNA-guided mRNA cleavage 58,59, but
        only one example of this mode of regulation has been found in animals 60. The
        diversity of RNA silencing phenomena suggests that other interesting findings
        await discovery. For example, the existence of an inheritance mechanism for the
        transmission of RNAi in C. elegans raises the question of whether natural small
        RNAs are transmitted in germ cells or other developmental cell lineages in other
        animals, including humans. Extrachromosomal inheritance of silencing patterns by
        means of small RNAs could provide sophisticated layers of gene regulation, at
        both post-transcriptional and chromatin-modifying levels. These small RNAs may
        be important in stem-cell maintenance and development, and differential
        localization of such RNAs may have a role in the generation of cellular
        diversity. It will be interesting to discover if the phenomenon of lateral
        transport of RNA from cell to cell, so far observed in plants 61,62 and C.
        elegans, is more widespread. As well as having a role in immunity, could
        'epigenetic RNA morphogens' allow cells to modulate the activity of developmentally
        important genes or mRNAs in neighbouring cells? This type of regulation might be
        particularly useful when cells, such as neurons, communicate at junctions that
        are far from the cell nucleus.

        The past ten years have seen an explosion in the number of noncoding RNAs found
        to orchestrate remarkably diverse functions 63,64. These functions include:
        sequence-specific modification of cellular RNAs guided by small nucleolar RNAs
        65; induction of chromosome-wide domains of chromatin condensation by the
        mammalian noncoding RNA Xist (X-inactive specific transcript)66; autosomal gene
        imprinting and silencing by noncoding mammalian Air (antisense IgF2r RNA)67; and
        finally sequence-directed cleavage and/or repression of target mRNAs and genes
        by miRNAs and siRNAs, discussed here and in the accompanying reviews. Some have
        likened this period to an RNA revolution. But considering the potential role of
        RNA as a primordial biopolymer of life, it is perhaps more apt to call it an RNA
        'revelation'. RNA is not taking over the cell - it has been in control all
        along. We just didn't realize it until now.

        Acknowledgements

        C.C.M. is an HHMI Assistant Investigator and is funded by the NIH. D.C. is
        supported by an NRSA postdoctoral fellowship.

        Competing interests statement

        The authors declare that they have no competing financial interests.

        1. Joyce, G. F. & Orgel, L. E. in The RNA World (eds Gestland, R. F., Cech, T.
        R. & Atkins, J. F.) 49-77 (Cold Spring Harbor Laboratory Press, New York, 1999).

        2. Gilbert, W. The RNA world. Nature 319, 618 (1986).

        3. Fire, A. et al. Potent and specific genetic interference by double-stranded
        RNA in Caenorhabditis elegans. Nature 391, 806-811 (1998). Ovid Full Text
        Bibliographic Links ExternalResolverBasic

        4. Proud, C. G. PKR: a new name and new roles. Trends Biochem. Sci. 20, 241-246
        (1995). Bibliographic Links ExternalResolverBasic

        5. Williams, B. R. Role of the double-stranded RNA-activated protein kinase
        (PKR) in cell regulation. Biochem. Soc. Trans. 25, 509-513 (1997).

        6. Guo, S. & Kemphues, K. J. par-1, a gene required for establishing polarity in
        C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically
        distributed. Cell 81, 611-620 (1995).

        7. Nellen, W. & Lichtenstein, C. What makes an mRNA anti-senseitive? Trends
        Biochem. Sci. 18, 419-423 (1993).

        8. Izant, J. G. & Weintraub, H. Inhibition of thymidine kinase gene expression
        by anti-sense RNA: a molecular approach to genetic analysis. Cell 36, 1007-1015
        (1984). Bibliographic Links ExternalResolverBasic

        9. Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance
        of RNAi in C. elegans. Science 287, 2494-2497 (2000).

        10. Rocheleau, C. E. et al. Wnt signaling and an APC-related gene specify
        endoderm in early C. elegans embryos. Cell 90, 707-716 (1997). Bibliographic
        Links ExternalResolverBasic

        11. Tabara, H., Grishok, A. & Mello, C. C. RNAi in C. elegans: soaking in the
        genome sequence. Science 282, 430-431 (1998). Bibliographic Links ExternalResolverBasic

        12. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395,
        854 (1998). Ovid Full Text Bibliographic Links ExternalResolverBasic

        13. Timmons, L., Court, D. L. & Fire, A. Ingestion of bacterially expressed
        dsRNAs can produce specific and potent genetic interference in Caenorhabditis
        elegans. Gene 263, 103-112 (2001). Bibliographic Links ExternalResolverBasic

        14. Tabara, H. et al. The rde-1 gene, RNA interference, and transposon silencing
        in C. elegans. Cell 99, 123-132 (1999).

        15. Schmidt, A. et al. Genetic and molecular characterization of sting, a gene
        involved in crystal formation and meiotic drive in the male germ line of
        Drosophila melanogaster. Genetics 151, 749-760 (1999). Bibliographic Links
        ExternalResolverBasic

        16. Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic
        tandem repeats and transposable elements in the D. melanogaster germline. Curr.
        Biol. 11, 1017-1027 (2001).

        17. Fagard, M., Boutet, S., Morel, J. B., Bellini, C. & Vaucheret, H. AGO1,
        QDE-2, and RDE-1 are related proteins required for post-transcriptional gene
        silencing in plants, quelling in fungi, and RNA interference in animals. Proc.
        Natl Acad. Sci. USA 97, 11650-11654 (2000). Bibliographic Links ExternalResolverBasic

        18. Catalanotto, C., Azzalin, G., Macino, G. & Cogoni, C. Gene silencing in
        worms and fungi. Nature 404, 245 (2000). Ovid Full Text Bibliographic Links
        ExternalResolverBasic

        19. de Carvalho, F. et al. Suppression of beta-1,3-glucanase transgene
        expression in homozygous plants. EMBO J. 11, 2595-2602 (1992). Bibliographic
        Links ExternalResolverBasic

        20. Napoli, C., Lemieux, C. & Jorgensen, R. Introduction of a chimeric chalcone
        synthase gene into petunia results in reversible co-suppression of homologous
        genes in trans. Plant Cell 2, 279-289 (1990). Bibliographic Links ExternalResolverBasic

        21. Romano, N. & Macino, G. Quelling: transient inactivation of gene expression
        in Neurospora crassa by transformation with homologous sequences. Mol.
        Microbiol. 6, 3343-3353 (1992). Bibliographic Links ExternalResolverBasic

        22. Kennerdell, J. R. & Carthew, R. W. Use of dsRNA-mediated genetic interference
        to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell
        95, 1017-1026 (1998). Bibliographic Links ExternalResolverBasic

        23. Ngo, H., Tschudi, C., Gull, K. & Ullu, E. Double-stranded RNA induces mRNA
        degradation in Trypanosoma brucei. Proc. Natl Acad. Sci. USA 95, 14687-14692
        (1998). Bibliographic Links ExternalResolverBasic

        24. Bosher, J. M. & Labouesse, M. RNA interference: genetic wand and genetic
        watchdog. Nature Cell Biol. 2, E31-E36 (2000).

        25. Hamilton, A. J. & Baulcombe, D. C. A species of small antisense RNA in
        post-transcriptional gene silencing in plants. Science 286, 950-952 (1999). Ovid
        Full Text Bibliographic Links ExternalResolverBasic

        26. Hammond, S. M., Bernstein, E., Beach, D. & Hannon, G. J. An RNA-directed
        nuclease mediates post-transcriptional gene silencing in Drosophila cells.
        Nature 404, 293-296 (2000). Ovid Full Text Bibliographic Links ExternalResolverBasic

        27. Zamore, P. D., Tuschl, T., Sharp, P. A. & Bartel, D. P. RNAi: double-stranded
        RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.
        Cell 101, 25-33 (2000). Bibliographic Links ExternalResolverBasic

        28. Parrish, S. & Fire, A. Distinct roles for RDE-1 and RDE-4 during RNA
        interference in Caenorhabditis elegans. RNA 7, 1397-1402 (2001). Bibliographic
        Links ExternalResolverBasic

        29. Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a
        bidentate ribonuclease in the initiation step of RNA interference. Nature 409,
        363-366 (2001). Ovid Full Text Bibliographic Links ExternalResolverBasic

        30. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference
        in cultured mammalian cells. Nature 411, 494-498 (2001).

        31. Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental
        timing in Caenorhabditis elegans. Nature 403, 901-906 (2000). Ovid Full Text
        Bibliographic Links ExternalResolverBasic

        32. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene
        lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75,
        843-854 (1993). Bibliographic Links ExternalResolverBasic

        33. Hutvagner, G. et al. A cellular function for the RNA-interference enzyme
        Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834-838
        (2001). Ovid Full Text Bibliographic Links ExternalResolverBasic

        34. Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis
        of small RNA involved in developmental timing in C. elegans. Genes Dev. 15,
        2654-2659 (2001).

        35. Grishok, A. et al. Genes and mechanisms related to RNA interference regulate
        expression of the small temporal RNAs that control C. elegans developmental
        timing. Cell 106, 23-34 (2001). Bibliographic Links ExternalResolverBasic

        36. Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3
        lysine-9 methylation by RNAi. Science 297, 1833-1837 (2002). Ovid Full Text
        Bibliographic Links ExternalResolverBasic

        37. Mochizuki, K., Fine, N. A., Fujisawa, T. & Gorovsky, M. A. Analysis of a
        piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena.
        Cell 110, 689-699 (2002). Bibliographic Links ExternalResolverBasic

        38. Waterhouse, P. M., Graham, M. W. & Wang, M. B. Virus resistance and gene
        silencing in plants can be induced by simultaneous expression of sense and
        antisense RNA. Proc. Natl Acad. Sci. USA 95, 13959-13964 (1998). Bibliographic
        Links ExternalResolverBasic

        39. Dalmay, T., Hamilton, A., Rudd, S., Angell, S. & Baulcombe, D. C. An
        RNA-dependent RNA polymerase gene in Arabidopsis is required for post-transcriptional
        gene silencing mediated by a transgene but not by a virus. Cell 101, 543-553
        (2000). Bibliographic Links ExternalResolverBasic

        40. Mourrain, P. et al. Arabidopsis SGS2 and SGS3 genes are required for
        post-transcriptional gene silencing and natural virus resistance. Cell 101,
        533-542 (2000). Bibliographic Links ExternalResolverBasic

        41. Cogoni, C. & Macino, G. Gene silencing in Neurospora crassa requires a
        protein homologous to RNA-dependent RNA polymerase. Nature 399, 166-169 (1999).
        Ovid Full Text Bibliographic Links ExternalResolverBasic

        42. Sijen, T. et al. On the role of RNA amplification in dsRNA-triggered gene
        silencing. Cell 107, 465-476 (2001). Bibliographic Links ExternalResolverBasic

        43. Smardon, A. et al. EGO-1 is related to RNA-directed RNA polymerase and
        functions in germ-line development and RNA interference in C. elegans. Curr.
        Biol. 10, 169-178 (2000).

        44. Schiebel, W., Haas, B., Marinkovic, S., Klanner, A. & Sanger, H. L.
        RNA-directed RNA polymerase from tomato leaves. II. Catalytic in vitro
        properties. J. Biol. Chem. 268, 11858-11867 (1993).

        45. Makeyev, E. V. & Bamford, D. H. Cellular RNA-dependent RNA polymerase
        involved in post-transcriptional gene silencing has two distinct activity modes.
        Mol. Cell 10, 1417-1427 (2002).

        46. Dougherty, W. G. & Parks, T. D. Transgenes and gene suppression: telling us
        something new? Curr. Opin. Cell Biol. 7, 399-405 (1995).

        47. Baulcombe, D. C. RNA as a target and an initiator of post-transcriptional
        gene silencing in transgenic plants. Plant Mol. Biol. 32, 79-88 (1996).
        Bibliographic Links ExternalResolverBasic

        48. Newport, J. Nuclear reconstitution in vitro: stages of assembly around
        protein-free DNA. Cell 48, 205-217 (1987). Bibliographic Links ExternalResolverBasic

        49. Tabara, H., Yigit, E., Siomi, H. & Mello, C. C. The dsRNA binding protein
        RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C.
        elegans. Cell 109, 861-871 (2002).

        50. Dernburg, A. F., Zalevsky, J., Colaiacovo, M. P. & Villeneuve, A. M.
        Transgene-mediated co-suppression in the C. elegans germ line. Genes Dev. 14,
        1578-1583 (2000).

        51. Ketting, R. F. & Plasterk, R. H. A genetic link between co-suppression and
        RNA interference in C. elegans. Nature 404, 296-298 (2000).

        52. Wassenegger, M., Heimes, S., Riedel, L. & Sanger, H. L. RNA-directed de novo
        methylation of genomic sequences in plants. Cell 76, 567-576 (1994). Bibliographic
        Links ExternalResolverBasic

        53. Mette, M. F. van der Winden, J., Matzke, M. A. & Matzke, A. J. Production of
        aberrant promoter transcripts contributes to methylation and silencing of
        unlinked homologous promoters in trans. EMBO J. 18, 241-248 (1999). Bibliographic
        Links ExternalResolverBasic

        54. Reinhart, B. J. & Bartel, D. P. Small RNAs correspond to centromere
        heterochromatic repeats. Science 297, 1831 (2002). Ovid Full Text Bibliographic
        Links ExternalResolverBasic

        55. Pal-Bhadra, M. et al. Heterochromatic silencing and HP1 localization in
        Drosophila are dependent on the RNAi machinery. Science 303, 669-672 (2004).

        56. Ketting, R. F., Haverkamp, T. H., van Luenen, H. G. & Plasterk, R. H. mut-7
        of C. elegans, required for transposon silencing and RNA interference, is a
        homolog of Werner syndrome helicase and RNaseD. Cell 99, 133-141 (1999).

        57. Sijen, T. & Plasterk, R. Transposon silencing in the Caenorhabditis elegans
        germ line by natural RNAi. Nature 426, 310-314 (2003).

        58. Llave, C., Xie, Z., Kasschau, K. D. & Carrington, J. C. Cleavage of
        Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science
        297, 2053-2056 (2002). Ovid Full Text Bibliographic Links ExternalResolverBasic

        59. Tang, G., Reinhart, B. J., Bartel, D. P. & Zamore, P. D. A biochemical
        framework for RNA silencing in plants. Genes Dev. 17, 49-63 (2003). Bibliographic
        Links ExternalResolverBasic

        60. Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8
        mRNA. Science 304, 594-596 (2004).

        61. Palauqui, J. C., Elmayan, T., Pollien, J. M. & Vaucheret, H. Systemic
        acquired silencing: transgene-specific post-transcriptional silencing is
        transmitted by grafting from silenced stocks to non-silenced scions. EMBO J. 16,
        4738-4745 (1997).

        62. Voinnet, O. & Baulcombe, D. C. Systemic signalling in gene silencing. Nature
        389, 553 (1997). Ovid Full Text Bibliographic Links ExternalResolverBasic

        63. Storz, G. An expanding universe of noncoding RNAs. Science 296, 1260-1263
        (2002). Bibliographic Links ExternalResolverBasic

        64. Morey, C. & Avner, P. Employment opportunities for non-coding RNAs. FEBS
        Lett. 567, 27-34 (2004).

        65. Kiss, T. Small nucleolar RNAs: an abundant group of noncoding RNAs with
        diverse cellular functions. Cell 109, 145-148 (2002). Bibliographic Links
        ExternalResolverBasic

        66. Wutz, A. & Jaenisch, R. A shift from reversible to irreversible X inactivation
        is triggered during ES cell differentiation. Mol. Cell 5, 695-705 (2000).
        Bibliographic Links ExternalResolverBasic

        67. Sleutels, F., Zwart, R. & Barlow, D. P. The non-coding Air RNA is required
        for silencing autosomal imprinted genes. Nature 415, 810-813 (2002).

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        Accession Number: 00006056-200409160-00057
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