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| Open AccessFIERY1 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 AccessDiscovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.
- Edmund C. Lee
- , Tania Valencia
- & Vishal Patel
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| Open AccessThe microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.
- Jian Huang
- , Lan Zhao
- & Di Chen
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Article
| Open AccessWwp2 maintains cartilage homeostasis through regulation of Adamts5
Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA
- Sho Mokuda
- , Ryo Nakamichi
- & Hiroshi Asahara
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Article
| Open AccessCirculating miR-103a-3p contributes to angiotensin II-induced renal inflammation and fibrosis via a SNRK/NF-κB/p65 regulatory axis
Angiotensin II is known to cause renal inflammation and fibrosis. Here Lu et al. show that levels of circulating miR-103a-3p are elevated in hypertensive nephropathy patients and in an animal model of angiotensin II-induced renal dysfunction, and that miR-103a-3p suppresses SNRK expression leading to the activation of the pro-inflammatory NF-κB pathway in glomerular endothelial cells.
- Qiulun Lu
- , Zejun Ma
- & Ming-Hui Zou
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Article
| Open AccessCrystal structure of the Lin28-interacting module of human terminal uridylyltransferase that regulates let-7 expression
Terminal uridylyltransferase 4/7 (TUT4/7) binds to Lin28 and modifies let-7 precursor (pre-let-7) to regulate cell differentiation and proliferation. Here the authors report the crystal structure of the N-terminal Lin28-interacting module of TUT4, showing a role of the N-terminal zinc finger domain in stabilizing the Lin28:pre-let-7:TUT4 ternary complex.
- Seisuke Yamashita
- , Takashi Nagaike
- & Kozo Tomita
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Article
| Open AccessCompetitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT
Competitive endogenous RNAs help to regulate biological processes by regulating miRNA activity levels. Here the author show TGFBI acts as a ceRNA for miR-21 in the epithelial-to-mesenchymal transition.
- Yuwei Liu
- , Mengzhu Xue
- & Peng Wang
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Article
| Open AccessGlobal identification of functional microRNA-mRNA interactions in Drosophila
MicroRNAs are mediators of post-transcriptional gene expression silencing. Here authors provide a transcriptome-wide map of miRNA target sites in Drosophila.
- Hans-Hermann Wessels
- , Svetlana Lebedeva
- & Uwe Ohler
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Article
| Open AccessPrecise tuning of gene expression levels in mammalian cells
Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.
- Yale S. Michaels
- , Mike B. Barnkob
- & Tudor A. Fulga
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Article
| Open AccessThe functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma
The delivery of single therapeutic microRNAs in brain cancers is challenging. Here, the authors engineer three neuronal microRNAs (miR-124, 128 and 137) into a cluster that, targeting oncogenic chromatin repressors, increases survival of GBM-bearing mice when combined with chemotherapy.
- Vivek Bhaskaran
- , Michal O. Nowicki
- & Pierpaolo Peruzzi
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Article
| Open AccessLEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation
miR-205 is known to have context-dependent tumor suppressive or oncogenic roles. Here, the authors report the host gene of miR-205, MIR205HG as a nuclear lincRNA that maintains the basal identity of prostate cell and prevents luminal cell differentiation via the repression of interferon responsive genes.
- Valentina Profumo
- , Barbara Forte
- & Paolo Gandellini
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Article
| Open AccessSingle-cell microRNA-mRNA co-sequencing reveals non-genetic heterogeneity and mechanisms of microRNA regulation
Single-cell RNA sequencing allows characterizing cell-to-cell heterogeneity at transcriptome scale. Here, the authors present an approach that enables microRNA and mRNA sequencing in the same single cell, providing insights into the origins of non-genetic cellular variability and mechanisms of miRNA regulation.
- Nayi Wang
- , Ji Zheng
- & Jun Lu
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Article
| Open AccessRoutes of Zika virus dissemination in the testis and epididymis of immunodeficient mice
The mechanisms of ZIKV persistence in the male reproductive tract (MRT) are poorly understood. Here, Tsetsarkin et al. applied microRNA-targeting approach to trace routes of ZIKV dissemination in the testis and epididymis and to generate immunogenic live-attenuated ZIKV vaccine candidate, restricted for MRT infection.
- Konstantin A. Tsetsarkin
- , Olga A. Maximova
- & Alexander G. Pletnev
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| Open AccessmiR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression
miR-122 is a highly expressed microRNA in the liver. Here the authors analyse the mouse liver microRNA landscape following depletion of miR-122 and the impact that this has on its target mRNAs.
- Paul N. Valdmanis
- , Hak Kyun Kim
- & Mark A. Kay
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Article
| Open AccessSynthetic RNA-based logic computation in mammalian cells
The construction of complex RNA-delivered genetic circuits in mammalian cells is challenging, though offers advantages over DNA circuits in clinical use. Here the authors construct a set of logic gates that respond to multiple miRNAs and demonstrate an apoptosis-regulatory AND gate.
- Satoshi Matsuura
- , Hiroki Ono
- & Hirohide Saito
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Article
| Open AccessTwo high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.
- Mary L. McMaster
- , Sonja I. Berndt
- & Neil E. Caporaso
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| Open AccessHepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.
- Cai Zhang
- , Joonbae Seo
- & Takahisa Nakamura
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Article
| Open AccessmicroCLIP super learning framework uncovers functional transcriptome-wide miRNA interactions
AGO-PAR-CLIP is widely used for high-throughput miRNA target characterization. Here, the authors show that the previously neglected non-T-to-C clusters denote functional miRNA binding events, and develop microCLIP, a super learning framework that accurately detects miRNA interactions.
- Maria D. Paraskevopoulou
- , Dimitra Karagkouni
- & Artemis G. Hatzigeorgiou
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| Open AccessEndogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradation
Via the target-directed miRNA degradation process, RNAs can induce degradation of miRNAs by binding with extensive complementarity. Here, the authors show Serpine1 mRNA as one such RNA that can control the levels of the endogenous miRNA miR-30b/c-5p by modulating miRNA degradation.
- Francesco Ghini
- , Carmela Rubolino
- & Francesco Nicassio
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| Open AccessmiR-103 promotes endothelial maladaptation by targeting lncWDR59
MicroRNAs play important roles in endothelial cells injury, proliferation and maladaptation by negatively regulating posttranscriptional gene expression. Here the authors uncover the role of the long non coding RNA lncWDR59, target of miR-103, in endothelial maladaptation.
- Lucia Natarelli
- , Claudia Geißler
- & Andreas Schober
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Article
| Open AccessA mixed antagonistic/synergistic miRNA repression model enables accurate predictions of multi-input miRNA sensor activity
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression but many quantitative aspects of miRNA biology remain to be elucidated. Based on a library of miRNA sensors, the authors quantify miRNA regulation at single cell level and develop a model to predict miRNA target interactions.
- Jeremy J. Gam
- , Jonathan Babb
- & Ron Weiss
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Article
| Open AccessParasitic insect-derived miRNAs modulate host development
The moth Plutella xylostella during its larval stage is the host of the endoparasitic wasp Cotesia vestalis. Here the authors show that the parasitoids deliver microRNAs to their hosts through their symbiotic virus and specialized cells leading to induced developmental delay.
- Zhi-zhi Wang
- , Xi-qian Ye
- & Xue-xin Chen
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Article
| Open AccessTet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter
Tet-mediated DNA oxidation converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is essential to regulate different biological processes. Here the authors show that Tet1 and Tet2 regulate mesenchymal stem cell and bone homeostasis through demethylation of P2rX7 promoter.
- Ruili Yang
- , Tingting Yu
- & Songtao Shi
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Article
| Open AccessDistinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
Feingold syndrome is a skeletal dysplasia caused by mutations in MYCN or MIR17HG, but it is not clear if these mutations lead to pathology via a common molecular mechanism. Here, the authors show that mutations in MIR17HG lead to upregulated TGF-β signaling in limb mesenchymal cells, while mutations in MYCN downregulate PI3K signaling.
- Fatemeh Mirzamohammadi
- , Anastasia Kozlova
- & Tatsuya Kobayashi
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Article
| Open AccessThe RNA-binding protein ARPP21 controls dendritic branching by functionally opposing the miRNA it hosts
Many microRNA encoding regions are within introns of other coding genes, and yet the molecular or functional interaction between the two is unclear. This study shows that miR-128′s function is opposed by its host gene ARPP21, and they have complementary effects on neuronal development.
- Frederick Rehfeld
- , Daniel Maticzka
- & F. Gregory Wulczyn
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Article
| Open AccessDirect conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue
At the site of injury, macrophages exit their characteristic phenotype undergoing direct conversion to fibroblasts. Keratinocyte-derived miR-21, packaged in extracellular vesicles, enables such plasticity which accounts for the vast majority of all fibroblasts in the granulation tissue.
- Mithun Sinha
- , Chandan K. Sen
- & Sashwati Roy
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Article
| Open AccessA cryptic RNA-binding domain mediates Syncrip recognition and exosomal partitioning of miRNA targets
Syncrip is a conserved RNA-binding protein that mediates selective miRNA loading into cell-secreted exosomes, which is important for cell–cell communication. Here the authors provide mechanistic insights into how Syncrip recognises its target miRNAs by combining NMR and crystallography.
- Fruzsina Hobor
- , Andre Dallmann
- & Andres Ramos
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Article
| Open AccessLoss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
During early postnatal development in mammals, cardiomyocytes exit the cell cycle, losing their regenerative capacity. Here the authors show that, following myocardial infarction, loss of microRNA-128 promotes cardiomyocyte proliferation and cardiac regeneration in adult mice partly via enhancing the expression of the chromatin modifier SUZ12.
- Wei Huang
- , Yuliang Feng
- & Yigang Wang
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Article
| Open AccessUltraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation
Ultraconserved RNAs are a class of long non-coding RNAs whose functions are yet to be identified. Here Guo and colleagues show that an ultraconserved RNA uc.372 promotes lipogenesis and lipid accumulation within the hepatocytes by suppressing the maturation of miR-195/miR-4668 that inhibits lipogenic gene expression.
- Jun Guo
- , Weiwei Fang
- & Jian Li
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Article
| Open AccessUnraveling the determinants of microRNA mediated regulation using a massively parallel reporter assay
MiRNAs are known regulators of gene expression. Here the authors perform a large-scale massively parallel reporter assay to investigate the effect of a large number of designed 3′ UTR sequences on reporter expression and asses how miRNA regulatory elements features affect miRNA mediated repression.
- Ilya Vainberg Slutskin
- , Shira Weingarten-Gabbay
- & Eran Segal
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Article
| Open AccessStress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival
Rbfox1, a pro-survival RNA-binding protein, is expressed in a complex manner and mediates diverse developmental processes. Here, the authors observe alternative splicing of Rbfox1 and stress-dependent regulation by miR-980 in Drosophila ovaries and Rbfox1 localisation in ribonucleoprotein granules in human cells.
- Mariya M. Kucherenko
- & Halyna R. Shcherbata
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Article
| Open AccessPTRE-seq reveals mechanism and interactions of RNA binding proteins and miRNAs
A large number of RNA binding proteins (RBPs) and miRNAs bind to the 3′ untranslated regions of mRNA, but methods to dissect their function and interactions are lacking. Here the authors introduce post-transcriptional regulatory element sequencing (PTRE-seq) to dissect sequence preferences, interactions and consequences of RBP and miRNA binding.
- Kyle A. Cottrell
- , Hemangi G. Chaudhari
- & Sergej Djuranovic
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Article
| Open AccessMechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling
Mesenchymal stem cell (MSC) fate can be mechanically regulated by substrate stiffness but this is difficult to control in a 3D hydrogel. Here the authors identify miRNAs that change expression in response to substrate stiffness and RhoA signalling and show that they can bias MSC fate in a 3D soft hydrogel.
- Jessica E. Frith
- , Gina D. Kusuma
- & Justin J. Cooper-White
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Article
| Open AccessIn situ functional dissection of RNA cis-regulatory elements by multiplex CRISPR-Cas9 genome engineering
RNA regulatory elements (RREs) are important post-transcriptional control features but studying them requires disrupting their activity without disturbing cellular homeostasis. Here the authors present GenERA, a CRISPR-Cas9 screening platform of in situ analysis of native RREs.
- Qianxin Wu
- , Quentin R. V. Ferry
- & Tudor A. Fulga
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Article
| Open AccessA miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning
White adipocytes can be stimulated to express thermogenic genes in a process known as beiging. Here, the authors show that miR-327 is downregulated during beiging, which releases FGF10 from inhibition and supports beige adipocyte formation via signaling through FGFR2.
- Carina Fischer
- , Takahiro Seki
- & Yihai Cao
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Article
| Open AccessCellular microRNA networks regulate host dependency of hepatitis C virus infection
Using genome-wide miRNA mimic and hairpin inhibitor screens, Li et al. identify 31 miRNAs that either inhibit or promote hepatitis C virus (HCV) replication at different steps of the viral life cycle. Furthermore, human liver biopsies show that HCV down-regulates identified miRNAs with antiviral function.
- Qisheng Li
- , Brianna Lowey
- & T. Jake Liang
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Article
| Open AccessExosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma
Exosomes are known to contain microRNAs (miRs). Here the authors show that dorsal root ganglion neurons release exosomes containing miR-21-5p, which contributes to inflammatory cell recruitment following peripheral nerve injury.
- Raffaele Simeoli
- , Karli Montague
- & Marzia Malcangio
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Article
| Open AccessHeme enables proper positioning of Drosha and DGCR8 on primary microRNAs
Drosha and DGCR8 constitute the core Microprocessor complex, which processes primary microRNAs (pri-miRs) into mature microRNAs. Here the authors show that heme is essential for the proper processing of pri-miRs by Drosha-DGCR8, and the molecular mechanism by which heme enhances processing fidelity.
- Alexander C. Partin
- , Tri D. Ngo
- & Yunsun Nam
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Article
| Open AccessCardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling
MicroRNA-29 is known to reduce collagen production in fibroblasts thereby inhibiting fibrosis in various organs. Here, Sassi et al. show that miR-29 can also enhance fibrotic signalling and pathological hypertrophy of the heart through its action in cardiomyocytes.
- Yassine Sassi
- , Petros Avramopoulos
- & Stefan Engelhardt
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Article
| Open AccessKSRP specifies monocytic and granulocytic differentiation through regulating miR-129 biogenesis and RUNX1 expression
RNA-binding proteins (RBPs) regulate RNA activity and are implicated in haematopoietic malignancies, but their role in myeloid cell specification is unclear. Here, the authors show a role for the RBP KSRP in promoting granulocyte fate over monocyte fate through the biogenesis of miR-129 and a decrease in RUNX1.
- Hongmei Zhao
- , Xiaoshuang Wang
- & Jia Yu
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Article
| Open AccessMicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors
Mesodermal iPSC-derived progenitors (MiPs) can regenerate both skeletal and cardiac muscle. Here, the authors show that a microRNA cocktail stimulates skeletal muscle differentiation and that human MiPs can engraft into striated muscle in mice.
- Giorgia Giacomazzi
- , Bryan Holvoet
- & Maurilio Sampaolesi
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Article
| Open AccessPost-transcriptional gene silencing mediated by microRNAs is controlled by nucleoplasmic Sfpq
MicroRNAs have been best characterized for their functions in the cytoplasm; however, there is growing evidence of a nuclear localized role. Here, the authors identify Sfpq as an Ago2-interacting protein that modulates miRNA activity in both the nucleus and cytoplasm.
- Silvia Bottini
- , Nedra Hamouda-Tekaya
- & Michele Trabucchi
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Article
| Open AccessHyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs
Hyperoxia contributes to lung injury in bronchopulmonary dysplasia. The authors show that hyperoxia increases miR-34a expression in human neonates and in mouse models, and that pathology is ameliorated by miR-34a inhibition or by administration of its target angiopoietin-1
- Mansoor Syed
- , Pragnya Das
- & Vineet Bhandari
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Article
| Open AccessThe circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency
Circular RNAs are abundant in the transcriptome and are implicated in the regulation of a range of biological processes. Here the authors identify circBIRC6 as a microRNA sponge that helps modulate human pluripotency and early lineage differentiation.
- Chun-Ying Yu
- , Tung-Cheng Li
- & Hung-Chih Kuo
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Article
| Open AccessCoding and noncoding landscape of extracellular RNA released by human glioma stem cells
While circulating DNA has been extensively explored as a potential cancer biomarker, RNA potential has been overlooked so far. Here the authors present a comprehensive analysis of extracellular RNA secreted by glioblastoma cells that could prove a valuable resource for biomarker discovery and a means of intercellular communication.
- Zhiyun Wei
- , Arsen O. Batagov
- & Anna M. Krichevsky
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Article
| Open AccessMammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism
APE1 plays an important role in the cellular response to oxidative stress, and mutations are linked to tumor progression and chemoresistance. Here, the authors characterize the interactions of APE1 with RNA and demonstrate a role in microRNA processing.
- Giulia Antoniali
- , Fabrizio Serra
- & Gianluca Tell
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Article
| Open AccessMicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology
Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models.
- Florence Sonneville
- , Manon Ruffin
- & Olivier Tabary
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Article
| Open AccessmiR-9a modulates maintenance and ageing of Drosophila germline stem cells by limiting N-cadherin expression
In the Drosophila testis, ageing leads to loss of germline stem cells. Here, the authors show that, during ageing in Drosophila, miR-9a is upregulated in male germline stem cells and regulates their proliferation by targeting N-cadherin.
- Yehonatan Epstein
- , Noam Perry
- & Hila Toledano
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Article
| Open AccessLet-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice
Hematopoietic stem and progenitor cells are generated first from the vascular endothelium of the dorsal aorta and then the fetal liver but what regulates this switch is unknown. Here, the authors show that changing miRNA biogenesis and leukotriene B4 signaling in mice modulates this switch in the niche.
- Xuan Jiang
- , John S. Hawkins
- & Akiko Hata