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Genetic activation of canonical RNA interference in mice [thymus]

ABSTRACT: Canonical RNA interference (RNAi) is sequence-specific mRNA degradation guided by small interfering RNAs (siRNAs) made from long double-stranded RNA (dsRNA) by RNase III Dicer. RNAi has different functions in eukaryotes including gene regulation, antiviral innate immunity or defense against transposable elements. In mammals, RNAi is constrained by inefficient cleavage of dsRNA by Dicer because it is adapted to produce microRNAs, a different class of small RNAs. An exception of the rule is highly active RNAi in mouse oocytes, which employs a truncated Dicer isoform (ΔHEL1). A homozygous mutation of murine Dicer to express only the truncated variant causes major dysregulation of microRNAs and perinatal lethality. Here, we report the phenotype and RNAi activity in DicerΔHEL1/wt mice, which are viable, fertile, slightly smaller, and show minimal miRNome changes. At the same time, endogenous siRNA levels are increased by an order of magnitude in DicerΔHEL1/wt mice. We show that siRNA abundance is limited by available dsRNA but not by the Protein Kinase R, an innate immunity factor shown to limit siRNA biogenesis in cultured cells. Using dsRNA expressed from a transgene, functional RNAi in vivo was successfully induced in the heart. DicerΔHEL1/wt mice thus represent a new model for researching mammalian canonical RNAi in vivo and offer an unprecedented platform for addressing earlier claims about its biological roles.

ORGANISM(S): Mus musculus

PROVIDER: GSE242870 | GEO | 2024/04/08

REPOSITORIES: GEO

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Genetic activation of canonical RNA interference in mice [heart]

Project description:Canonical RNA interference (RNAi) is sequence-specific mRNA degradation guided by small interfering RNAs (siRNAs) made from long double-stranded RNA (dsRNA) by RNase III Dicer. RNAi has different functions in eukaryotes including gene regulation, antiviral innate immunity or defense against transposable elements. In mammals, RNAi is constrained by inefficient cleavage of dsRNA by Dicer because it is adapted to produce microRNAs, a different class of small RNAs. An exception of the rule is highly active RNAi in mouse oocytes, which employs a truncated Dicer isoform (ΔHEL1). A homozygous mutation of murine Dicer to express only the truncated variant causes major dysregulation of microRNAs and perinatal lethality. Here, we report the phenotype and RNAi activity in DicerΔHEL1/wt mice, which are viable, fertile, slightly smaller, and show minimal miRNome changes. At the same time, endogenous siRNA levels are increased by an order of magnitude in DicerΔHEL1/wt mice. We show that siRNA abundance is limited by available dsRNA but not by the Protein Kinase R, an innate immunity factor shown to limit siRNA biogenesis in cultured cells. Using dsRNA expressed from a transgene, functional RNAi in vivo was successfully induced in the heart. DicerΔHEL1/wt mice thus represent a new model for researching mammalian canonical RNAi in vivo and offer an unprecedented platform for addressing earlier claims about its biological roles.

2024-04-08 | GSE242867 | GEO

Genetic activation of canonical RNA interference in mice [brain]

2024-04-08 | GSE242866 | GEO

Genetic activation of canonical RNA interference in mice [spleen]

2024-04-08 | GSE242869 | GEO

Genetic activation of canonical RNA interference in mice [liver]

2024-04-08 | GSE242868 | GEO

Genetic activation of canonical RNA interference in mice [skeletal muscle]

2024-04-08 | GSE259395 | GEO

Human virus-derived small RNAs can confer antiviral immunity in mammals

Project description:RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates, however whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner, loaded into AGO, and were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer-deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals.

2017-08-01 | GSE99252 | GEO

Proteins that interact physically with Drosophila blanks

Project description:RNA interference targets aberrant transcripts with cognate small interfering RNAs, which derive from double-stranded RNA precursors through nucleolytic processing. Several functional screens have identified Drosophila blanks/lump (CG10630) as a facilitator of RNAi in cultured cells, yet its molecular function has remained unknown. The protein carries two dsRNA binding domains (dsRBD) and blanks mutant males have a spermatogenesis defect. We demonstrate that blanks selectively boosts RNAi triggered by dsRNA of nuclear origin. Blanks binds dsRNA in vitro, shuttles between nucleus and cytoplasm and the abundance of certain endogenous siRNAs is reduced in blanks mutant testes. Transgenic expression of a Blanks protein variant with increased nuclear retention reduces endogenous siRNA abundance unless the protein also carries a mutation that prevents binding of dsRNA to the second dsRBD. Blanks thus facilitates the export of dsRNA to the cytoplasm for further processing by the canonical RNAi machinery. In contrast, rescue of male fertility in blanks mutant animals was independent of RNA binding to the second dsRBD, consistent with a previous report that linked fertility to the first dsRBD of Blanks. The role of blanks in spermatogenesis appears thus unrelated to its role in dsRNA export.

2020-05-26 | PXD013792 | Pride

The RIG-I like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells.

Project description:In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I like receptor (RLR) family , which signal to induce production of type I interferons (IFN). These key anti-viral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We identify Dicer as an LGP2-associated protein and show that LGP2 inhibits Dicer cleavage of dsRNA into siRNAs both in vitro and in vivo. Further, we show that in cells lacking an IFN response, ectopic expression of LGP2 interferes with RNAi-dependent suppression of gene expression. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs.

2018-01-17 | PXD008364 | Pride

Human nuclear Dicer restricts the deleterious accumulation of endogenous double strand RNA

Project description:Dicer is a central enzymatic player in RNA interference (RNAi) pathways that acts to regulate gene expression in nearly all eukaryotes. Although the cytoplasmic function of Dicer is well documented in mammals, there is little known about any possible nuclear function. Here we show that Dicer is present in both the nucleus and cytoplasm, but that its nuclear levels are tightly regulated. In its nuclear manifestation Dicer interacts with RNA polymerase II (Pol II) at actively-transcribed gene loci. Loss of Dicer causes the appearance of endogenous dsRNA, leading to induction of the interferon response pathway and consequent cell death. Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping non-coding RNA transcription units. Failure to do so has catastrophic effects on cell function. Taken together, we present here a micro (mi)RNA independent role for human nuclear Dicer. DICER ChIP-seq profile in wt 293 HEK cells, and dsRNA-seq profile in wt and DICER-depleted 293 HEK cells

2014-04-10 | E-GEOD-56648 | biostudies-arrayexpress

Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage

Project description:The endonuclease Dicer is a key component of the human RNA interference (RNAi) pathway and known for its role in cytoplasmic micro RNA (miRNA) production. Recent findings suggest that non-canonical Dicer generates small non-coding RNA (ncRNA) to mediate the DNA damage response (DDR). Here we show that human Dicer is phosphorylated in the platform-PAZ-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks (DSBs). We further demonstrate that turnover of damage-induced nuclear dsRNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage-induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes spontaneous DNA damage and delays DNA repair. Taken together, we place Dicer in context of the DDR by demonstrating DNA damage-inducible phospho-switch that causes localised processing of nuclear dsRNA by p-Dicer to promote DNA repair.

2018-12-08 | GSE75892 | GEO

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