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| Open AccessWTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and Nucleus pulposus cell senescence contributes a lot to its progression. Here, the authors reveal WTAP-mediated m6A modification of lncRNA NORAD promotes IVDD.
- Gaocai Li
- , Liang Ma
- & Cao Yang
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Article
| Open AccessSingle-molecule imaging of microRNA-mediated gene silencing in cells
For decades, miRNAs have been studied primarily by ensemble methods, where a bulk collection of molecules is measured outside cells. Here, Kobayashi and Singer report methods to image miRNA function at the single-molecule level inside cells.
- Hotaka Kobayashi
- & Robert H. Singer
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Article
| Open AccessStructural analysis of 3’UTRs in insect flaviviruses reveals novel determinants of sfRNA biogenesis and provides new insights into flavivirus evolution
Subgenomic flaviviral RNAs (sfRNAs) are produced by pathogenic flaviviruses to counteract the host antiviral response. sfRNAs are products of incomplete degradation of viral RNA by the host exoribonuclease XRN1 which stalls on XRN1-resistant structural elements (xrRNAs) in the 3‟UTR. Here, Slonchak et al. identify xrRNAs for mosquito-specific flaviviruses, characterize their ability to stall XRN1 and produce sfRNAs, and apply structure-based phylogenetic analysis to provide evidence for evolutionary selection of these elements.
- Andrii Slonchak
- , Rhys Parry
- & Alexander A. Khromykh
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Article
| Open AccessThe core and accessory Hfq interactomes across Pseudomonas aeruginosa lineages
Protein Hfq regulates bacterial mRNA translation and stability by interacting with mRNAs and small noncoding RNAs. Here, the authors identify Hfq-interacting RNAs in three strains representing major phylogenetic lineages of Pseudomonas aeruginosa, highlighting intra-species diversity in post-transcriptional regulatory networks.
- Julian Trouillon
- , Kook Han
- & Stephen Lory
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Article
| Open AccessKastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis
A number of testes-specific lncRNAs have been annotated but their roles remain largely unexplored. Here the authors identify two small peptides encoded by the lncRNA Gm9999, Kastor and Polluks, both of which are required for male fertility in mice.
- Shintaro Mise
- , Akinobu Matsumoto
- & Keiichi I. Nakayama
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Article
| Open AccessOsteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo
Bone remodeling involves a switch between bone formation and resorption, but the mechanisms is unclear. Here, the authors show that intercellular communication via extracellular vesicles secreted by mature osteoblasts is a key factor for the switching, via a microRNA-mediated mechanism.
- Maki Uenaka
- , Erika Yamashita
- & Masaru Ishii
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Article
| Open AccessSmall RNA pathways in the nematode Ascaris in the absence of piRNAs
The parasitic nematode Ascaris lacks piRNAs. Here the authors compare Argonaute proteins and small RNAs from C. elegans and Ascaris, expanding our understanding of the conservation, divergence, and flexibility of Argonautes and small RNA pathways in nematodes.
- Maxim V. Zagoskin
- , Jianbin Wang
- & Richard E. Davis
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Article
| Open AccessA disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
Mutations in the non-coding RNA RMRP cause primary immunodeficiency. Robertson et al show that a disease-associated mutation in RMRP impairs pre-ribosomal RNA processing and reduces ribosome abundance, establishing this disorder as a ribosomopathy.
- Nic Robertson
- , Vadim Shchepachev
- & David Tollervey
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Article
| Open AccessMicroRNA-365 regulates human cardiac action potential duration
An abnormal cardiac action potential underlies different types of cardiac arrhythmias. Here the authors show that microRNA-365 regulates the cardiac action potential by modulating key cardiac repolarizing channels.
- Dena Esfandyari
- , Bio Maria Ghéo Idrissou
- & Stefan Engelhardt
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Article
| Open AccessThe 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 AccessAn anionic ligand snap-locks a long-range interaction in a magnesium-folded riboswitch
A single molecule fluorescence study revealed three dynamically interconverting conformations of the fluoride riboswitch from Bacillus cereus, where an anionic ligand snap-locks a docked conformation through a long-range interaction necessary for downstream gene regulation.
- Rajeev Yadav
- , Julia R. Widom
- & Nils G. Walter
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Article
| Open AccessThe long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer
Elevated expression of long noncoding RNA H19 is seen in clinical samples of neuroendocrine prostate cancer (PCa). Here the authors show H19 promotes plasticity from luminal to neuroendocrine by epigenetic reprogramming.
- Neha Singh
- , Varune R. Ramnarine
- & Andrew S. Kraft
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Article
| Open AccessThe long non-coding RNA landscape of Candida yeast pathogens
Long non-coding RNAs (lncRNAs) play roles in key cellular processes, but remain largely unexplored in fungal pathogens such as Candida. Here, Hovhannisyan and Gabaldón analyze thousands of sequencing datasets to infer and characterize the lncRNA repertoires of five Candida species, paving the way for their future functional characterization.
- Hrant Hovhannisyan
- & Toni Gabaldón
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Article
| Open AccessHuman miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy is a myopathy caused by aberrant de-repression of the DUX4 gene. Here, the authors show that miR-675 inhibits DUX4 expression and protects muscles from DUX4-mediated cell death when administered to mice using AAV, and that upregulation of miR-675 via small molecules inhibits DUX4 and DUX4-associated biomarkers in myotubes derived from patients.
- Nizar Y. Saad
- , Mustafa Al-Kharsan
- & Scott Q. Harper
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Article
| Open AccessAngiogenin mediates paternal inflammation-induced metabolic disorders in offspring through sperm tsRNAs
Paternal environmental inputs can influence various phenotypes in offspring, with important implications for basic biology and public health. Here the authors show that Ang-mediated biogenesis of 5′-tsRNAs in sperm contributes to paternal inflammation-induced metabolic disorders in offspring.
- Yanwen Zhang
- , Li Ren
- & Bin He
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Article
| Open AccessA structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome
The RNA genome of the Hepatitis C Virus binds to the liver-specific miR122. Here the authors report the crystal structure of the Ago2:miR122:HCV complex showing that the viral RNA’s structural element traps the Ago2:miR-122 complex on the 5’ end of the viral genome to protect it from degradation.
- Luca F. R. Gebert
- , Mansun Law
- & Ian J. MacRae
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Article
| Open AccessModulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage
Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.
- Pietro Carotenuto
- , Francesco Amato
- & Chiara Braconi
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Article
| Open AccessDHX15-independent roles for TFIP11 in U6 snRNA modification, U4/U6.U5 tri-snRNP assembly and pre-mRNA splicing fidelity
In yeast, TFIP11 and DHX15 promote the disassembly of spliceosome complex after splicing is completed. Here the authors show that human TFIP11 functions independently of DHX15 and is required for U6 snRNA 2’-O-methylation and U4/U6.U5 tri-snRNP assembly.
- Amandine Duchemin
- , Tina O’Grady
- & Denis Mottet
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Article
| Open AccessThe parent-of-origin lncRNA MISSEN regulates rice endosperm development
The cereal endosperm is a major determinant of seed size and shape. Here the authors show that a lncRNA, MISSEN, is expressed from the maternally derived allele in rice seeds and regulates a helicase family protein to support efficient nuclear division, distribution and cellularization in the endosperm.
- Yan-Fei Zhou
- , Yu-Chan Zhang
- & Yue-Qin Chen
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Article
| Open AccessAssociation of snR190 snoRNA chaperone with early pre-60S particles is regulated by the RNA helicase Dbp7 in yeast
The molecular events underlying the assembly and maturation of the early pre-60S particles during eukaryotic ribosome synthesis are not well understood. Here, the authors combine yeast genetics and biochemical experiments to characterise the functions of two important players of eukaryotic ribosome biogenesis, the box C/D snoRNP snR190 and the helicase Dbp7, which both interact. They show that the snR190 snoRNA acts as a RNA chaperone that assists the structuring of the 25S rRNA during the maturation of early pre-60S particles and that Dbp7 is important for facilitating remodeling events in the peptidyl transferase center region of the 25S rRNAs during the maturation of early pre-60S particles.
- Mariam Jaafar
- , Julia Contreras
- & Anthony K. Henras
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Article
| Open AccessEndurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism
Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.
- Julie Massart
- , Rasmus J. O. Sjögren
- & Anna Krook
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Article
| Open AccessStructure of human cytomegalovirus virion reveals host tRNA binding to capsid-associated tegument protein pp150
Here, cryo-EM reconstructions of human cytomegalovirus (HCMV) virions reveal host tRNAs associated with the virion’s capsid-bound tegument protein, pp150. tRNA recruitment is mediated by the interactions specific for HCMV only, suggesting the explanation for the absence of such tRNA densities in related herpesviruses.
- Yun-Tao Liu
- , David Strugatsky
- & Z. Hong Zhou
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Article
| Open AccessLoss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis
Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice.
- Arthur C. Sletten
- , Jessica W. Davidson
- & Jean E. Schaffer
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Article
| Open AccessPre-meiotic 21-nucleotide reproductive phasiRNAs emerged in seed plants and diversified in flowering plants
Pre-meiotic anthers of monocots accumulate phased, small interfering RNAs (phasiRNAs) that are absent in many well-studied model eudicots. Here, the authors show that such 21-nt phasiRNAs are in fact present in diverse eudicot species including strawberry, in which production is triggered by miR11308.
- Suresh Pokhrel
- , Kun Huang
- & Blake C. Meyers
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Article
| Open AccessA microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration
Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.
- Andrea Raso
- , Ellen Dirkx
- & Leon J. De Windt
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Article
| Open AccessNanopore sequencing of brain-derived full-length circRNAs reveals circRNA-specific exon usage, intron retention and microexons
Short-read sequencing methods cannot delineate internal exon composition and alternative splicing events of long and multi-exon circular RNAs (circRNAs). Here the authors provide a global map of full-length circRNAs by long-read sequencing in human and mouse brain samples.
- Karim Rahimi
- , Morten T. Venø
- & Jørgen Kjems
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Article
| Open AccessPuf6 primes 60S pre-ribosome nuclear export at low temperature
Ribosome biogenesis is crucially dependent on proper rRNA folding, a process assisted by chaperones. Here the authors reveal how Puf6 promotes correct rRNA folding at low temperature, a condition where mis-paired RNA folding intermediates frequently accumulate.
- Stefan Gerhardy
- , Michaela Oborská-Oplová
- & Vikram Govind Panse
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Article
| Open AccessRNase κ promotes robust piRNA production by generating 2′,3′-cyclic phosphate-containing precursors
Mature piRNAs are produced from long single-stranded precursor RNAs. Here the authors show that RNase κ generates 2′,3′-cyclic phosphate-containing piRNA precursors and promotes piRNA production.
- Megumi Shigematsu
- , Takuya Kawamura
- & Yohei Kirino
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Article
| Open AccessSmall RNA mediated gradual control of lipopolysaccharide biosynthesis affects antibiotic resistance in Helicobacter pylori
The small RNA RepG modulates expression of chemotaxis receptor TlpB in Helicobacter pylori by targeting a length-variable G-repeat in the tlpB mRNA. Here, Pernitzsch et al. show that RepG also gradually controls lipopolysaccharide biosynthesis, antibiotic susceptibility, and in-vivo colonization of the stomach, by regulating a gene that is co-transcribed with tlpB.
- Sandy R. Pernitzsch
- , Mona Alzheimer
- & Cynthia M. Sharma
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Article
| Open AccessArginine 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 AccessBoth microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
- Yoshiaki Ito
- , Tokio Matsuzaki
- & Hiroshi Asahara
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Article
| Open AccessBinding of guide piRNA triggers methylation of the unstructured N-terminal region of Aub leading to assembly of the piRNA amplification complex
PIWI protein contains arginine rich motifs that are post-translationally modified to symmetrically methylated arginine (sDMA) residues. Here the authors show that piRNA loading into Aub triggers sDMA modification which is recognized by Krimper to promote formation of Krimper-Aub-Ago3 complex for piRNA amplification in Drosophila.
- Xiawei Huang
- , Hongmiao Hu
- & Sisi Li
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Article
| Open AccessLong noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons
Long noncoding RNAs (lncRNAs) are known to regulate the DNA damage response (DDR), however their role in the brain is less well studied. Here, the authors demonstrate a neuron-specific role for Brain Specific DNA-damage Related lncRNA1 (BS-DRL1) and show BS-DRL1 modulates DDR by interacting with HMGB1 in a cell-type specific manner.
- Min-Min Lou
- , Xiao-Qiang Tang
- & Wen-Yuan Wang
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Article
| Open AccessThe long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice
Beta-cell function is often impaired in obesity through incompletely understood mechanisms. Here the authors show that the long noncoding RNA βFaar is reduced by diet-induced obesity in mice, which leads to impaired beta-cell function via miR-138-5p and survival via TRAF3 Interacting Protein 2.
- Fangfang Zhang
- , Yue Yang
- & Liang Jin
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Article
| Open AccessA 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 AccessThe pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis
Genomic amplification of chromosome 3q often encodes proteins that contribute to cancer development. Here the authors identify a non-coding product of the 3q region, the lncRNA PLANE that promotes tumorigenesis through the deregulation of transcriptional corepressor NCOR2 pre-mRNA splicing.
- Liu Teng
- , Yu Chen Feng
- & Xu Dong Zhang
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Article
| Open AccessTERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
TERRA RNA has previously been linked to Alternative lengthening of telomeres (ALT). Here the authors developed a tool to rapidly inhibit TERRA transcription from different chromosome ends in an ALT cell line to show that TERRA transcription actively promotes break induced replication (BIR) and destabilizes telomere integrity in ALT cells.
- Bruno Silva
- , Rajika Arora
- & Claus M. Azzalin
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Article
| Open AccessA pig BodyMap transcriptome reveals diverse tissue physiologies and evolutionary dynamics of transcription
A comprehensive transcriptomic survey of the pig could enable mechanistic understanding of tissue specialization and accelerate its use as a biomedical model. Here the authors characterize four distinct transcript types in 31 adult pig tissues to dissect their distinct structural and transcriptional features and uncover transcriptomic variability related to tissue physiology.
- Long Jin
- , Qianzi Tang
- & Mingzhou Li
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Article
| Open AccessSingle-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum
miRNA profiling from patient blood can be used for cancer diagnosis. Here the authors present an electro-optical nanopore sensing platform which allows sensitive and specific miRNA detection directly in human serum and apply to monitoring of miR-141-3p and miR-375-3p in different stage of prostate cancer.
- Shenglin Cai
- , Thomas Pataillot-Meakin
- & Joshua B. Edel
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Article
| Open AccessBRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.
- Jekaterina Vohhodina
- , Liana J. Goehring
- & David M. Livingston
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Article
| Open AccessTranslation and codon usage regulate Argonaute slicer activity to trigger small RNA biogenesis
22G-RNAs are single-stranded antisense small RNAs that are expressed in C. elegans germline. Here the authors show that CSR-1 dependent 22G-RNAs are produced in the cytosol on mRNAs actively engaged in translation and that codon usage of an mRNA regulates the biogenesis of CSR-1 dependent 22G-RNAs.
- Meetali Singh
- , Eric Cornes
- & Germano Cecere
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Article
| Open AccessReprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells
Cells infected with pathogens can release signals that instruct neighbouring cells to mount an immune response or that reduce these cells’ susceptibility to infection. Here, Aguilar et al. show the opposite effect: cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells by activating their ER-stress response.
- Carmen Aguilar
- , Susana Costa
- & Ana Eulalio
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Article
| Open AccessmiR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Homeostasis of the intestinal epithelium is crucial for the maintenance of the epithelial barrier. Here, the authors show that mir-802 ablation in the mouse intestine impairs enterocyte differentiation and glucose absorption, enhances Paneth cell function by increasing Tmed9-mediated defensin secretion, and increases epithelial cell turnover.
- Algera Goga
- , Büsra Yagabasan
- & Markus Stoffel
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Article
| Open AccessUBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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Article
| Open AccessThe genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation
The epigenome has been shown to change with age, potentially impacting on ageing-related disease. Here the authors investigate the DNA methylation state of the genomic loci of human tRNA and observe enrichment for age-related DNA hypermethylation at tRNA loci.
- Richard J. Acton
- , Wei Yuan
- & Christopher G. Bell
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Article
| Open AccessThe lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis
Long noncoding RNAs (lncRNAs) have been shown to play a role in cardiac physiology and disease. Here the authors identify the lncRNA Caren as a cytoplasmic RNA that decreases the translation of a distant gene encoding Hint1, thereby maintaining cardiomyocyte function due to inactivation of the DNA damage response and activation of mitochondrial bioenergetics.
- Michio Sato
- , Tsuyoshi Kadomatsu
- & Yuichi Oike
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Article
| Open AccessMastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.
- Do-Kyun Kim
- , Geethani Bandara
- & Ana Olivera
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Article
| Open AccessThe long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.
- Marta Montes
- , Michal Lubas
- & Anders H. Lund
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Article
| Open AccessRNA binding of Hfq monomers promotes RelA-mediated hexamerization in a limiting Hfq environment
RelA stimulates RyhB small RNA–target mRNA interaction by promoting assembly of Hfq monomers into hexamers. Here the authors show that RelA-mediated Hfq hexamerization requires an initial binding of RNA to Hfq monomers.
- Pallabi Basu
- , Maya Elgrably-Weiss
- & Shoshy Altuvia