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Article
| Open Access
HRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1
Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.
- Shihui Chen
- & Carolyn M. Phillips
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Article
| Open Access
Spatial distribution of three ARGONAUTEs regulates the anther phasiRNA pathway
Spatial and intracellular control of three Argonaute proteins is crucial for anther development in rice. Two, AGO1b and AGO1d, may carry 1st uracil–phasiRNAs as mobile signals from the somatic cell layers to the germ cells in the anther.
- Hinako Tamotsu
- , Koji Koizumi
- & Reina Komiya
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Article
| Open Access
The CLASSY family controls tissue-specific DNA methylation patterns in Arabidopsis
CLASSY (CLSY) proteins regulate DNA methylation at specific loci in the Arabidopsis genome. Here the authors show that the CLSYs also control tissue-specific DNA methylation, including at siren loci in ovules, and that the lack of an individual CLSYs can shift the epigenetic landscape between tissues.
- Ming Zhou
- , Ceyda Coruh
- & Julie A. Law
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Article
| Open Access
Arginine methylation promotes siRNA-binding specificity for a spermatogenesis-specific isoform of the Argonaute protein CSR-1
The Argonaute protein CSR-1 is essential for fertility and viability in C. elegans. Here the authors show that CSR-1A isoform associates preferentially with small RNAs mapping to spermatogenesis-specific genes while CSR-1B isoform binds small RNAs mapping to oogenesis-specific genes. Arginine methylation of CSR-1A promotes small RNA-binding specificity.
- Dieu An H. Nguyen
- & Carolyn M. Phillips
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Article
| Open Access
A smart multiantenna gene theranostic system based on the programmed assembly of hypoxia-related siRNAs
The therapeutic application of small interfering RNA (siRNA) is challenging due to its non-specific targeting and delivery issues. Here, the authors report an endogenous micro-RNA guided and hybridisation chain reaction-promoted siRNA delivery system encapsulated in tumour-derived extracellular vesicles, with cancer-specific activation, and achieve silencing of hypoxia-related genes.
- Xue Gong
- , Haizhou Wang
- & Fuan Wang
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Article
| Open Access
Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation
Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.
- Lucía Barbier-Torres
- , Karen A. Fortner
- & Mercedes Rincón
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Article
| Open Access
Dicer-like 5 deficiency confers temperature-sensitive male sterility in maize
Small RNAs act to regulate gene or transposon activity during plant development. Here, the authors show that maize Dicer-like 5 is required for 24-nt phased, secondary small interfering RNA production in anthers and that dicer-like 5 mutants show abnormal tapetal development and temperature-sensitive sterility.
- Chong Teng
- , Han Zhang
- & Virginia Walbot
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Article
| Open Access
FIERY1 promotes microRNA accumulation by suppressing rRNA-derived small interfering RNAs in Arabidopsis
Arabidopsis AGO1 binds both microRNA (miRNA) and endogenous small interfering RNA (siRNA). Here the authors show that 5′−3′ RNA degradation suppresses siRNA biogenesis from ribosomal RNA to prevent overloading of AGO1 with ribosomal siRNA and maintain miRNA-directed post translational gene silencing.
- Chenjiang You
- , Wenrong He
- & Beixin Mo
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Article
| Open Access
RST1 and RIPR connect the cytosolic RNA exosome to the Ski complex in Arabidopsis
Cytosolic RNA degradation by the RNA exosome requires the Ski complex. Here the authors show that the proteins RST1 and RIPR assist the RNA exosome and the Ski complex in RNA degradation, thereby preventing the production of secondary siRNAs from endogenous mRNAs.
- Heike Lange
- , Simon Y. A. Ndecky
- & Dominique Gagliardi
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Article
| Open Access
Multifunctional cationic nanosystems for nucleic acid therapy of thoracic aortic dissection
Thoracic aortic dissection has a high fatality rate and no effective treatment. Here, the authors develop cationic nanoparticles for the delivery of miR-145 and show that they stabilize vascular structures and prevent further deterioration of the aorta in mouse models of the disease.
- Chen Xu
- , Yanzhenzi Zhang
- & Fu-Jian Xu
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Article
| Open Access
Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis
The adaptor protein SHN3 suppresses new bone formation by controlling osteoblast activity. Here, the authors show that ablation of SHN3 function, either genetically or by delivering an artificial miRNA via AAV9, rescues bone loss in osteoporotic mice, and show that engineering of the AAV9 capsid improves targeting to bone
- Yeon-Suk Yang
- , Jun Xie
- & Jae-Hyuck Shim
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Article
| Open Access
Design of a platform technology for systemic delivery of siRNA to tumours using rolling circle transcription
RNA interference has provided a promising tool to suppress the expression of specific genes associated with human diseases. Here, the authors present a platform technology for the systemic delivery of siRNA to tumour sites using rolling circle transcription.
- Mihue Jang
- , Jong Hwan Kim
- & Hyung Jun Ahn
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Article
| Open Access
Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
Therapeutic oligonucleotides can be made more stable by substituting their achiral phosphodiester groups for chiral phosphorothioate linkages. Here, the authors present a synthesis of phosphorothioated RNAs, where the activator controls strand stereochemistry, and also the activity of assembled siRNAs.
- Hartmut Jahns
- , Martina Roos
- & Jonathan Hall
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Article
| Open Access
Cell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles
A potential drug should specifically interact with its intended target in order to limit unwanted side effects. Here, the authors fabricate a biodegradable polymer nanoparticle with a fluorescent hepatic uptake transporter ligand to achieve targeted in vivosiRNA delivery and imaging of delivery.
- Adrian T. Press
- , Anja Traeger
- & Michael Bauer
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2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity
Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al. chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.
- Sherry Y. Wu
- , Xianbin Yang
- & Anil K. Sood
Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy