Slicing and Dicing for Small RNAs

Birchler, James A.; Kavi, Harsh H.

doi:10.1126/science.1159018

Cited by 32 publications

(24 citation statements)

References 11 publications

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“…2A). Mice contain a single Dicer gene that is required to generate mature miRNAs (Birchler and Kavi 2008). Inducible ablation of Dicer in adult hearts overcame previously described early developmental defects (Chen et al 2008) and allowed timed analysis to distinguish primary effects from secondary compensatory changes.…”

Section: Resultsmentioning

confidence: 99%

MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development

Kalsotra¹,

Wang²,

Li³

et al. 2010

Genes Dev.

117

126

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Alternative splicing transitions have been identified recently as a conserved component of vertebrate heart remodeling during postnatal development. Here we report that the targeted deletion of Dicer, specifically in adult mouse myocardium, reveals the role of microRNAs (miRNAs) in regulating networks of postnatal splicing transitions and in maintaining adult splicing programs. We demonstrate a direct role for miR-23a/b in the dramatic postnatal down-regulation of CUGBP and ETR-3-like factor (CELF) proteins that regulate nearly half of developmentally regulated splicing transitions in the heart. These findings define a hierarchy in which rapid postnatal upregulation of specific miRNAs controls expression of alternative splicing regulators and the subsequent splicing transitions of their downstream targets.Supplemental material is available at http://www.genesdev.org.Received December 7, 2009; revised version accepted February 17, 2010. MicroRNAs (miRNAs) are key components of posttranscriptional gene regulation with diverse roles in tissue development, differentiation, and homeostasis (van Rooij et al. 2007;Zhao et al. 2007;Bartel 2009). Mature miRNAs are formed by two sequential processing reactions: Primary transcripts of miRNA genes are first cleaved into hairpin-containing intermediates (pre-miRNAs) by the Drosha microprocessor complex, and pre-miRNAs are then processed into mature miRNAs by Dicer (Kim 2005). While miRNA-mediated regulation stimulates quantitative changes in protein and mRNA expression (Baek et al. 2008;Selbach et al. 2008), alternative pre-mRNA splicing controls qualitative gene output in the expression of diverse mRNA isoforms (Blencowe 2006). Recent genome-wide studies revealed that >90% of human intron-containing genes are alternatively spliced, and more than half of alternative splicing events differ between tissues, revealing an extensive level of regulation Pan et al. 2008;Wang et al. 2008).The mammalian heart undergoes a period of dramatic remodeling during the first 3 wk after birth that requires transcriptional and post-transcriptional regulatory programs not yet fully understood (Xu et al. 2005;Olson 2006). We recently identified a conserved set of alternative splicing transitions during mouse heart development, and demonstrated that nearly half are responsive to the CUGBP and ETR-3-like factor (CELF) family of splicing regulators . Two CELF proteins, CUGBP1 and CUGBP2, are highly expressed in the fetal heart, but are down-regulated >10 fold within 3 wk after birth without a change in mRNA levels.Here we used targeted deletion of the Dicer gene specifically in adult mouse myocardium to test the role of miRNAs in the mechanism of CELF protein downregulation during postnatal development. Both CELF proteins were dramatically up-regulated within 2 d of Dicer knockout, as was a subset of five other splicing regulators, while spliceosomal components and an additional set of splicing regulators were not affected. Using multiple independent assays, including antagomir delivery to adul...

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Section: Resultsmentioning

confidence: 99%

MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development

Kalsotra¹,

Wang²,

Li³

et al. 2010

Genes Dev.

117

126

View full text Add to dashboard Cite

show abstract

“…Consequently, they were suggested to form part of the silencing mechanism for pseudogenes and transposons. 28,29 Importantly, endosiRNAs were also detected from convergently transcribed genomic loci, although at a much lower level. 24 These observations concur with our own work on a bi-directionally transcribed gene locus (Solute carrier 34a, Slc34a).…”

Section: Biological Implications For Endo-natsmentioning

confidence: 99%

“…Endo-siRNAs were only discovered recently and their biological role is largely speculative. 28 They could, however, provide keys to answer the nagging question: What good are siRNAs for the organism itself?…”

Section: Are All Endo-nats Genomic Regulators?mentioning

confidence: 99%

What do natural antisense transcripts regulate?

Werner

Carlile²,

Swan³

2009

RNA Biology

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“…(D) The time-course generation of vp28-siRNA in response to WSSV infection. At different times after infection of shrimp with WSSV (0,2,6,12,24, 48, and 72 h p.i. ), tissues were collected and subjected to small RNA isolation and northern blot.…”

mentioning

confidence: 99%

Host defense against DNA virus infection in shrimp is mediated by the siRNA pathway

Huang¹,

Zhang²

2012

Eur J Immunol

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The RNA interference (RNAi) system of eukaryotes using siRNAs has been documented as an immune response against invasion by RNA viruses. However, whether the siRNA pathway can be triggered by the infection with DNA viruses in animals remains to be investigated. In the present study, we show that Marsupenaeus japonicus shrimp can generate an antiviral siRNA (vp28-siRNA) in response to infection by a double-stranded DNA virus, white spot syndrome virus (WSSV). After challenging with WSSV, vp28-siRNA is detected in all the WSSV-infected organs and tissues of shrimp as early as 24 h postinfection (p.i.). The results indicate that the host Dicer2 and Ago2 proteins are required for the biogenesis and function of vp28-siRNA, respectively. We show further that vp28-siRNA predominates in the cytoplasm of shrimp hemocytes at 48 h p.i. Knockdown of Dicer2 by special siRNA or inhibition of vp28-siRNA with locked nucleic acid antisense oligonucleotides both lead to a significant increase in WSSV copy number at 24-48 h p.i. Our study highlights a novel aspect of the siRNA pathway in the immune response of animals against infection by DNA viruses.Keywords: Ago2 r Dicer2 r Shrimp r siRNA r WSSV See accompanying Commentary by Sabin and Cherry IntroductionRNA interference (RNAi) is an evolutionarily conserved mechanism that involves the triggering of adaptive immune responses against RNA viruses by small interfering RNAs (siRNAs) in eukaryotes [1][2][3][4][5]. The double-stranded (ds) siRNAs of approximately 21 base pairs in length are generated from dsRNAs, such as those from RNA viruses, endogenous transposons, or other genomic regions that produce transcripts capable of forming dsRNA structures [6][7][8][9][10][11]. The siRNAs processed from RNA viruses provide antiviral defense in plants and animals through the cleavage and degradation of target viral mRNA [12][13][14][15].The mechanism by which eukaryotic organisms use RNA silencing to combat virus infections was first discovered in plants and invertebrates [16,17]. In plants, either RNA or DNA virus infecCorrespondence: Prof. Xiaobo Zhang e-mail: zxb0812@zju.edu.cn tion can trigger host Dicer-like proteins to produce virus-derived siRNAs (viRNAs) that destroy the RNAs of invading viruses [18][19][20]. To further amplify these antiviral molecules, secondary viRNAs are produced by RNA-dependent RNA polymerases (RdRPs) that generate more dsRNAs from these cleaved transcript fragments, suggesting that the formation of dsRNA is necessary to initiate the synthesis of antiviral siRNA [21,22]. Similar amplification of viRNA with RdRPs was also discovered in Caenorhabditis elegans [5]. However, no RdRP homologs that convert single-stranded (ss) viral transcripts to dsRNAs have been identified thus far in flies or mammals. Recently, DNA viRNA were identified in mosquitoes using high-throughput sequencing of small RNAs, but the underlying mechanism of viral siRNA biogenesis remains unclear [23]. Although the antiviral activities of siRNAs against RNA viruses have been well documented,...

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Slicing and Dicing for Small RNAs

Cited by 32 publications

References 11 publications

MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development

MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development

What do natural antisense transcripts regulate?

Host defense against DNA virus infection in shrimp is mediated by the siRNA pathway

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