Two RNAi Complexes, RITS and RDRC, Physically Interact and Localize to Noncoding Centromeric RNAs

Motamedi, Maryam; Verdel, André; Colmenares, Serafin U.; Gerber, Scott A.; Gygi, Steven P.; Moazed, Danesh

doi:10.1016/j.cell.2004.11.034

Cited by 513 publications

(772 citation statements)

References 49 publications

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“…44 An emerging view is that the methylated H3-K9 mark, which is established by the trans-acting RNAi machinery and/or DNA-binding factors, stably tethers RITS (RNA-induced transcriptional gene silencing) to chromatin, which in turn engages RDRC (RNA-dependent RNA polymerase) and perhaps Dicer to process nascent transcripts into siRNAs. 45 These siRNAs feed back to trigger further recruitment of heterochromatin machinery. If and how siRNAs localize histone-modifying activities, in particular HMTs, remains to be determined.…”

Section: Wildmentioning

confidence: 99%

Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

Tabolacci¹,

Moscato

Zalfa

et al. 2008

Eur J Hum Genet

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Fragile X syndrome (FXS) is caused by the expansion of a CGG repeat in the 5 0 UTR of the FMR1 gene and the subsequent methylation of all CpG sites in the promoter region. We recently identified, in unrelated FXS families, two rare males with an unmethylated full mutation, that is, with an expanded CGG repeat (4200 triplets) lacking the typical CpG methylation in the FMR1 promoter. These individuals are not mentally retarded and do not appear to be mosaic for premutation or methylated full mutation alleles. We established lymphoblastoid and fibroblast cell lines that showed essentially normal levels of the FMR1-mRNA but reduced translational efficiency of the corresponding mRNA. Epigenetic analysis of the FMR1 gene demonstrated the lack of DNA methylation and a methylation pattern of lysines 4 and 27 on histone H3 similar to that of normal controls, in accordance with normal transcription levels and consistent with a euchromatic configuration. On the other hand, histone H3/H4 acetylation and lysine 9 methylation on histone H3 were similar to those of typical FXS cell lines, suggesting that these epigenetic changes are not sufficient for FMR1 gene inactivation. These findings demonstrate remarkable consistency and suggest a common genetic mechanism causing this rare FMR1 epigenotype. The discovery of such a mechanism may be important in view of therapeutic attempts to convert methylated into unmethylated full mutations, restoring the expression of the FMR1 gene.

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Section: Wildmentioning

confidence: 99%

Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

Tabolacci¹,

Moscato

Zalfa

et al. 2008

Eur J Hum Genet

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“…Rhino, in turn, interacts indirectly with Cutoff through the protein Deadlock. This is reminiscent of transcriptional gene silencing in S. pombe, with dual recognition of loci by Ago1 and chromodomain protein Chp1 in the RNA-induced transcriptional silencing (RITS) complex [56]. Ultimately, the current model proposes that Cutoff protects cluster transcripts from transcriptionally-coupled pre-mRNA processing (such as polyA-tailing and splicing) [54,55] consequently favoring these transcripts to undergo piRNA rather than mRNA processing.…”

Section: Other Components Of Micro and Sirna Biogenesismentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

216

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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“…In S. pombe, there is an absolute requirement for H3K9me and the responsible KMT Clr4 KMT1 in silencing [87,88]. Transcription by pol II at centromeric repeats has been demonstrated to lead to recruitment of factors that modify chromatin, resulting in generation of the H3K9me mark [77].…”

Section: Silencing Requires Transcriptionmentioning

confidence: 99%

“…The RITS complex recruits the Rdp1-containing complex RDRC (RNA-Directed RNA polymerase Complex) [87]. RDRC consists of Rdp1, Hrr1, a helicase that interacts with Ago1 in a Clr4-dependent manner, and Cid12 which is a polyA polymerase.…”

Section: Wwwcell-researchcom | Cell Researchmentioning

confidence: 99%

Epigenetics: heterochromatin meets RNAi

2009

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The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference (RNAi) targets homologous DNA sequences and recruits factors that modify the chromatin, commonly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymerases in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.

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Two RNAi Complexes, RITS and RDRC, Physically Interact and Localize to Noncoding Centromeric RNAs

Cited by 513 publications

References 49 publications

Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Epigenetics: heterochromatin meets RNAi

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