Transcriptional silencing of a transgene by RNAi in the soma of<i>C. elegans</i>

Grishok, Alla; Sinskey, Jina L.; Sharp, Phillip A.

doi:10.1101/gad.1247705

Cited by 163 publications

(150 citation statements)

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“…This prediction is based on the role of rde-4 and zfp-1 genes in our characterized system of transcriptional silencing of a transgene (6), the demonstrated requirement of RDE-4 for production of at least some endo-siRNAs (3,26) and on the predicted nuclear function of the ZFP-1 protein. ZFP-1 is a homolog of mammalian protein AF10, which causes myeloid leukemia when fused to MLL (27).…”

Section: Discussionmentioning

confidence: 99%

“…Also, we found that RNAi pathway genes and lin-35(Rb) synergize in repressing the intestinal cell divisions and in repressing the cyclin E gene (cye-1) expression, likely through cooperative inhibition of cye-1 transcription (7). Two chromatinrelated genes, zfp-1 and gfl-1, promote the RNAi process in C. elegans, either directly or indirectly, they also contribute to RNAi-TGS of a repetitive transgene (6,8,9). Interestingly, both genes were also found to antagonize the repressive function of LIN-35(Rb) (10,11).…”

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confidence: 99%

“…We have characterized a system of RNAi-induced transcriptional gene silencing (RNAi-TGS) of a repetitive transgene expressed in the soma of C. elegans (6). Also, we found that RNAi pathway genes and lin-35(Rb) synergize in repressing the intestinal cell divisions and in repressing the cyclin E gene (cye-1) expression, likely through cooperative inhibition of cye-1 transcription (7).…”

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RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans

Grishok

Hoersch

Sharp

2008

Proc. Natl. Acad. Sci. U.S.A.

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In Caenorhabditis elegans , a vast number of endogenous short RNAs corresponding to thousands of genes have been discovered recently. This finding suggests that these short interfering RNAs (siRNAs) may contribute to regulation of many developmental and other signaling pathways in addition to silencing viruses and transposons. Here, we present a microarray analysis of gene expression in RNA interference (RNAi)-related mutants rde-4 , zfp-1 , and alg-1 and the retinoblastoma (Rb) mutant lin-35 . We found that a component of Dicer complex RDE-4 and a chromatin-related zinc finger protein ZFP-1, not implicated in endogenous RNAi, regulate overlapping sets of genes. Notably, genes a) up-regulated in the rde-4 and zfp-1 mutants and b) up-regulated in the lin-35 (Rb) mutant, but not the down-regulated genes are highly represented in the set of genes with corresponding endogenous siRNAs (endo-siRNAs). Our study suggests that endogenous siRNAs cooperate with chromatin factors, either C. elegans ortholog of acute lymphoblastic leukemia-1 (ALL-1)-fused gene from chromosome 10 (AF10), ZFP-1, or tumor suppressor Rb, to regulate overlapping sets of genes and predicts a large role for RNAi-based chromatin silencing in control of gene expression in C. elegans .

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Section: Discussionmentioning

confidence: 99%

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RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans

Grishok

Hoersch

Sharp

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…RNAi-dependent transcriptional silencing has been demonstrated to entail histone modifications, such as H3K9 methylation, in eukaryotes belonging to at least three different supergroups (Table 2). Moreover, siRNA-triggered transcriptional repression occurs in organisms that lack cytosine DNA methylation such as S. pombe and C. elegans (Grishok et al 2005;Martienssen et al 2005;Ponger and Li 2005;Robert et al 2005;Volpe et al 2002) and in organisms with very limited DNA methylation such as T. brucei and D. melanogaster (Kavi et al 2005;Pal-Bhadra et al 2004;Ponger and Li 2005;Shi et al 2004;Ullu et al 2004). In contrast, RNA-directed DNA methylation has, thus far, only been demonstrated in plants and mammals (Kawasaki and Taira 2004;Matzke and Birchler 2005;Morris et al 2004) and the role of DNA methylation in this type of gene silencing is somewhat debatable in mammals (Ting et al 2005;Weinberg et al 2006).…”

Section: Additional (Derived?) Functions Of the Rnai Machinerymentioning

confidence: 99%

On the origin and functions of RNA-mediated silencing: from protists to man

2006

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Double-stranded RNA has been shown to induce gene silencing in diverse eukaryotes and by a variety of pathways. We have examined the taxonomic distribution and the phylogenetic relationship of key components of the RNA interference (RNAi) machinery in members of five eukaryotic supergroups. On the basis of the parsimony principle, our analyses suggest that a relatively complex RNAi machinery was already present in the last common ancestor of eukaryotes and consisted, at a minimum, of one Argonautelike polypeptide, one Piwi-like protein, one Dicer, and one RNAdependent RNA polymerase. As proposed before, the ancestral (but non-essential) role of these components may have been in defense responses against genomic parasites such as transposable elements and viruses. From a mechanistic perspective, the RNAi machinery in the eukaryotic ancestor may have been capable of both small-RNA-guided transcript degradation as well as transcriptional repression, most likely through histone modifications. Both roles appear to be widespread among living eukaryotes and this diversification of function could account for the evolutionary conservation of duplicated Argonaute-Piwi proteins. In contrast, additional RNAi-mediated pathways such as RNA-directed DNA methylation, programmed genome rearrangements, meiotic silencing by unpaired DNA, and miRNA-mediated gene regulation may have evolved independently in specific lineages.

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“…Dcr-1 is accompanied by different Argonaute proteins, Rde-1 and Alg-1͞2, in the RNAi and miRNA pathways, respectively (6,8). Surprisingly, both RNAi and miRNA pathway genes affect RNAi-induced transcriptional gene silencing (RNAi-TGS) in the soma of C. elegans (9).…”

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Negative regulation of nuclear divisions in Caenorhabditis elegans by retinoblastoma and RNA interference-related genes

Grishok

Sharp

2005

Proc. Natl. Acad. Sci. U.S.A.

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Short RNA regulatory molecules, microRNAs, and short interfering RNAs participate in a range of developmental gene networks by base-pairing with their target sequences. Consistent with these findings, genes required for the biogenesis and function of short interfering RNAs and microRNAs, dicer (dcr-1 in Caenorhabditis elegans) and argonaute homologs, are essential for development in diverse organisms, including C. elegans. We demonstrate that genes required for the function of short RNAs synergize with the retinoblastoma tumor suppressor homolog lin-35 in negative regulation of the nuclear divisions in the intestine of C. elegans. The level of cyclin E (cye-1) expression is critical for nuclear divisions in the intestine and is elevated in double mutants in lin-35 and RNA interference pathway genes. We propose that RNA interferencerelated pathways cooperate with retinoblastoma in transcriptional repression of endogenous genes, an example being cyclin E.cyclin E R NA interference (RNAi) was originally discovered in Caenorhabditis elegans as a mechanism of posttranscriptional gene silencing induced by exogenous dsRNA (1). It is now known that RNAi-related mechanisms play roles in inhibition of target mRNA translation (2), mRNA degradation (3), or repression of transcription (4). Processing of dsRNA in the first step of RNAi and processing of all C. elegans microRNA (miRNA) precursors requires dcr-1 (5-7). Dcr-1 is accompanied by different Argonaute proteins, Rde-1 and Alg-1͞2, in the RNAi and miRNA pathways, respectively (6,8). Surprisingly, both RNAi and miRNA pathway genes affect RNAi-induced transcriptional gene silencing (RNAi-TGS) in the soma of C. elegans (9).A majority of human cancers have a mutation inactivating the retinoblastoma (Rb) pathway (10, 11). Three Rb-related genes are expressed in vertebrate cells, but only one member of this family exists in C. elegans (12). In both types of organisms Rb-related activities are thought to control cell proliferation and development primarily by suppressing transcription at promoters near their binding sites. The specificity of Rb proteins is mediated by their association with the E2F family of DNA-binding proteins, which heterodimerize with the DP protein (13). Proteins associated with the Rb protein can inhibit transcription by modifications of chromatin. Specifically, Rb complexes are associated with histone deacetylases and chromatin remodeling proteins (13,14). Further, in differentiating cells, some Rbcontaining complexes are associated with histone methyltransferase Suv39h, which catalyzes H3 lysine 9 (H3-K9) methylation, promoting heterochromatin formation (15, 16).RNAi-mediated gene silencing can also function through repressive chromatin modifications in some organisms (4, 17). In fission yeast, short interfering RNAs pair in a complex of proteins with nascent transcripts to direct modifications of chromatin (18). Similar processes are thought to be active in plants (17). In C. elegans, RNAi-induced transcriptional transgene silencing has been observed...

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Transcriptional silencing of a transgene by RNAi in the soma ofC. elegans

Cited by 163 publications

References 60 publications

RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans

RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans

On the origin and functions of RNA-mediated silencing: from protists to man

Negative regulation of nuclear divisions in Caenorhabditis elegans by retinoblastoma and RNA interference-related genes

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