Modulation of Splicing by Single-Stranded Silencing RNAs

Liu, Jing; Hu, Jiaxin; Hicks, Jessica A.; Prakash, Thazha P.; Corey, David R.

doi:10.1089/nat.2014.0527

Cited by 21 publications

(22 citation statements)

References 37 publications

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“…In this study we focused on AGO2 because it is (i) a central factor for RNAi activity Rand et al 2004; Joshua-Tor and Hannon 2011); (ii) present in mammalian cell nuclei (Robb et al 2005;Ohrt et al 2012;Gagnon et al 2014a); and (iii) can modulate RNA-mediated control of transcription (Janowski et al 2005;Li et al 2006;Chu et al 2010;Huang et al 2010;Matsui et al 2013) and splicing (Liu et al 2012(Liu et al , 2015. RNA sequencing (RNA-seq) of nuclear RNAs that interact with AGO2 has revealed read clusters near intronexon junctions and at gene promoters (Chu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells

Kalantari

Hicks

et al. 2016

RNA

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Argonaute 2 (AGO2), the catalytic engine of RNAi, is typically associated with inhibition of translation in the cytoplasm. AGO2 has also been implicated in nuclear processes including transcription and splicing. There has been little insight into AGO2's nuclear interactions or how they might differ relative to cytoplasm. Here we investigate the interactions of cytoplasmic and nuclear AGO2 using semi-quantitative mass spectrometry. Mass spectrometry often reveals long lists of candidate proteins, complicating efforts to rigorously discriminate true interacting partners from artifacts. We prioritized candidates using orthogonal analytical strategies that compare replicate mass spectra of proteins associated with Flag-tagged and endogenous AGO2. Interactions with TRNC6A, TRNC6B, TNRC6C, and AGO3 are conserved between nuclei and cytoplasm. TAR binding protein interacted stably with cytoplasmic AGO2 but not nuclear AGO2, consistent with strand loading in the cytoplasm. Our data suggest that interactions between functionally important components of RNAi machinery are conserved between the nucleus and cytoplasm but that accessory proteins differ. Orthogonal analysis of mass spectra is a powerful approach to streamlining identification of protein partners.

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Section: Discussionmentioning

confidence: 99%

“…AGO2 can act in conjunction with guide RNAs to regulate transcription (Chu et al 2010;Matsui et al 2013) and splicing (AmeyarZazoua et al 2012;Liu et al 2015) in human cells. While RNAi can be active in cell nuclei, there are also significant differences.…”

Section: Introductionmentioning

confidence: 99%

Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells

Kalantari

Hicks

et al. 2016

RNA

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“…Moreover, the two studies are in agreement in proposing an antisense transcript, rather than pre-mRNA, as RISC-mediated splicing control target. In contrast, Liu et al [77,79] have suggested that both duplexes, RNA molecules and single stranded RNAs complementary to sequences near exon/intron junctions, may modulate splicing by leading AGO2 to pre-mRNAs. These small oligonucleotides would induce exon skipping in a chromatin modification independent manner.…”

Section: Mirnas: Nuclear Functionsmentioning

confidence: 99%

MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions

Catalanotto

Cogoni

Zardo

2016

IJMS

980

675

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The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several types of ncRNAs. Based on their precursor structures, biogenesis pathways and modes of action, ncRNAs are classified as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs), promoter associate RNAs (pRNAs), small nucleolar RNAs (snoRNAs) and sno-derived RNAs. Among these, miRNAs appear as important cytoplasmic regulators of gene expression. miRNAs act as post-transcriptional regulators of their messenger RNA (mRNA) targets via mRNA degradation and/or translational repression. However, it is becoming evident that miRNAs also have specific nuclear functions. Among these, the most studied and debated activity is the miRNA-guided transcriptional control of gene expression. Although available data detail quite precisely the effectors of this activity, the mechanisms by which miRNAs identify their gene targets to control transcription are still a matter of debate. Here, we focus on nuclear functions of miRNAs and on alternative mechanisms of target recognition, at the promoter lavel, by miRNAs in carrying out transcriptional gene silencing.

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“…As 60% of point mutations associated with diseases have been found to be related to splicing defects (Jensen et al, 2009), several methods have been developed to modify alternative splicing. For example, duplex RNAs have also been used to modify alternative splicing in mammalian cells (Liu et al, 2012), and a method of using single stranded siRNAs has been developed to modify the splicing of a Dystrophin RNA, which is associated with Duchene muscular dystrophy (Liu et al, 2015). The results of our work introduce the possibility of microRNAs as tools to modulating alternative splicing.…”

Section: Microrna Mir-1002 Is a Part Of The Stress Response Networkmentioning

confidence: 92%

MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing

Park

Tao

Brazill

et al. 2019

Preprint

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Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stemloop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.

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Modulation of Splicing by Single-Stranded Silencing RNAs

Cited by 21 publications

References 37 publications

Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells

Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells

MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions

MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing

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