RNA Biology
- miR‐9‐5p suppresses pro‐fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2
- Marta Fierro‐Fernández1,
- Óscar Busnadiego1,
- Pilar Sandoval1,
- Cristina Espinosa‐Díez1,
- Eva Blanco‐Ruiz1,
- Macarena Rodríguez2,
- Héctor Pian2,
- Ricardo Ramos3,
- Manuel López‐Cabrera1,
- Maria Laura García‐Bermejo2 and
- Santiago Lamas*,1
- 1Department of Cell Biology and Immunology, Centro de Biología Molecular “Severo Ochoa” (CBMSO), Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid, Spain
- 2Department of Pathology, Hospital Universitario “Ramón y Cajal”, IRYCIS, Madrid, Spain
- 3Genomic Facility, Parque Científico de Madrid, Madrid, Spain
- ↵*Corresponding author. Tel: +34 911964455; Fax: +34 911964420; E‐mail: slamas{at}cbm.csic.es
miR‐9‐5p is discovered as an anti‐fibrotic miRNA that targets TGBR2 and NOX4 to inhibit the transformation of fibroblasts into myofibroblasts. TGF‐β1 itself is pro‐fibrogenic, but promotes miR‐9‐5p expression, thus inducing inhibition of its own pro‐fibrogenic role.
Synopsis
miR‐9‐5p is discovered as an anti‐fibrotic miRNA that targets TGBR2 and NOX4 to inhibit the transformation of fibroblasts into myofibroblasts. TGF‐β1 itself is pro‐fibrogenic, but promotes miR‐9‐5p expression, thus inducing inhibition of its own pro‐fibrogenic role.
Reactive oxygen species and TGF‐β1 induce miR‐9‐5p expression.
miR‐9‐5p inhibits TGFBR2 and NOX4 expression by binding to their 3′‐UTRs.
miR‐9‐5p inhibits TGF‐β‐mediated pro‐fibrogenic signaling in human lung fibroblasts and attenuates the development of experimental pulmonary fibrosis.
Peritoneal mesothelial fibrogenesis is also significantly reduced by miR‐9‐5p.
EMBO Reports (2015) 16: 1358–1377
- Received May 28, 2015.
- Revision received July 17, 2015.
- Accepted July 20, 2015.
- © 2015 The Authors
- MicroRNA‐455 regulates brown adipogenesis via a novel HIF1an‐AMPK‐PGC1α signaling network
- Hongbin Zhang*,1,2,
- Meiping Guan1,3,
- Kristy L Townsend1,
- Tian Lian Huang1,
- Ding An1,
- Xu Yan1,
- Ruidan Xue1,
- Tim J Schulz1,4,
- Jonathon Winnay1,
- Marcelo Mori1,5,
- Michael F Hirshman1,
- Karsten Kristiansen6,
- John S Tsang7,
- Andrew P White8,
- Aaron M Cypess1,
- Laurie J Goodyear1 and
- Yu‐Hua Tseng*,1,9
- 1Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
- 2Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- 3Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- 4Adipocyte Development Research Group, German Institute of Human Nutrition, Potsdam, Germany
- 5Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil
- 6Department of Biology, University of Copenhagen, Copenhagen, Denmark
- 7Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases (NIAID) and Trans‐NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA
- 8Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- 9Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
- ↵*
Corresponding author. Tel: +1 45 3533 0484; E‐mail: hongbin{at}sund.ku.dk
Corresponding author. Tel: +1 617 309 1967; Fax: +1 617 309 2650; E‐mail: yu-hua.tseng{at}joslin.harvard.edu
miR‐455 promotes brown adipocyte differentiation and thermogenesis by targeting the key adipogenic inhibitors Necdin and Runx1t1 and by inducing a HIF1an‐AMPK‐PGC1α signaling cascade stimulating mitochondria biogenesis.
Synopsis
miR‐455 promotes brown adipocyte differentiation and thermogenesis by targeting the key adipogenic inhibitors Necdin and Runx1t1 and by inducing a HIF1an‐AMPK‐PGC1α signaling cascade stimulating mitochondria biogenesis.
miR‐455 is expressed in brown adipose tissue and induced by cold.
Fat‐specific miR‐455 transgenic mice show browning of subcutaneous white fat upon cold exposure.
miR‐455 induces brown/beige adipogenesis by targeting key brown adipogenic inhibitors such as Runx1t1 and Necdin.
miR‐455 activates a HIF1an‐AMPK‐PGC1α signaling cascade that promotes thermogenesis.
EMBO Reports (2015) 16: 1378–1393
- Received June 11, 2015.
- Revision received July 19, 2015.
- Accepted July 24, 2015.
- © 2015 The Authors
- DGCR8 is essential for tumor progression following PTEN loss in the prostate
- Cassandra D Belair*,1,2,3,
- Alireza Paikari1,2,
- Felix Moltzahn1,3,
- Archana Shenoy1,3,
- Christina Yau4,5,
- Marc Dall'Era3,
- Jeff Simko3,6,
- Christopher Benz4,5 and
- Robert Blelloch1,2,3,6
- 1The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California – San Francisco, San Francisco, CA, USA
- 2Center for Reproductive Sciences, University of California – San Francisco, San Francisco, CA, USA
- 3Department of Urology, University of California – San Francisco, San Francisco, CA, USA
- 4Department of Medicine, University of California – San Francisco, San Francisco, CA, USA
- 5Buck Institute for Research on Aging, Novato, CA, USA
- 6Department of Anatomic Pathology, University of California – San Francisco, San Francisco, CA, USA
- ↵*Corresponding author. Tel: +1 415 476 2838; E‐mail: cassandra.belair{at}ucsf.edu
This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia.
Synopsis
This study uncovers an essential role for the microRNA biogenesis factor DGCR8 in prostate tumor progression following PTEN loss. The simultaneous deletion of Dgcr8 and Pten allows early progression to hyperplasia but not later progression to dysplasia.
DGCR8 loss prevents growth and progression of Pten null prostate tumors.
DGCR8 loss mainly inhibits expansion of the basal cell compartment of the Pten null epithelium.
Small RNA sequencing reveals numerous microRNA level changes associated with PTEN loss.
Increases in DGCR8 are associated with AKT activation in a large cohort of human patient samples.
EMBO Reports (2015) 16: 1219–1232
- Received November 25, 2014.
- Revision received June 24, 2015.
- Accepted June 27, 2015.
- © 2015 The Authors
- The RNA surveillance complex Pelo‐Hbs1 is required for transposon silencing in the Drosophila germline
- Fu Yang1,2,
- Rui Zhao2,
- Xiaofeng Fang3,4,
- Huanwei Huang2,
- Yang Xuan2,
- Yanting Ma2,
- Hongyan Chen2,
- Tao Cai2,
- Yijun Qi3,4 and
- Rongwen Xi*,2
- 1College of Life Sciences Beijing Normal University, Beijing, China
- 2National Institute of Biological Sciences, Beijing, China
- 3Tsinghua‐Peking Center for Life Sciences, Beijing, China
- 4Center for Plant Biology, School of Life Sciences Tsinghua University, Beijing, China
- ↵*Corresponding author. Tel: +86 10 80723241; Fax: +86 10 80723249; E‐mail: xirongwen{at}nibs.ac.cn
The Pelo (Dom34)‐Hbs1 mRNA surveillance complex is required for transposon silencing in the Drosophila germline, which reveals a novel mechanism of transposon silencing possibly at the translational level.
Synopsis
The Pelo (Dom34)‐Hbs1 mRNA surveillance complex is required for transposon silencing in the Drosophila germline, which reveals a novel mechanism of transposon silencing possibly at the translational level.
Loss of Pelo causes up‐regulation of specific transposable elements (TEs) in both ovaries and testes.
Pelo is not required in the piRNA pathway.
Pelo functionally interacts with Hbs1 in TE silencing, and RpS30a overexpression partially rescues TE silencing defects in pelo mutants.
EMBO Reports (2015) 16: 965–974
- Received January 13, 2015.
- Revision received May 27, 2015.
- Accepted June 2, 2015.
- © 2015 The Authors
- RNA metabolism: putting the brake on the UPR
- Amado Carreras‐Sureda1,2 and
- Claudio Hetz (chetz{at}med.uchile.cl) (chetz{at}hsph.harvard.edu) 1,2,3
- 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- 2Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- 3Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA
The unfolded protein response (UPR) is a major signaling cascade that determines cell fate under conditions of endoplasmic reticulum (ER) stress. The kinetics and amplitude of UPR responses are tightly controlled by several feedback loops and the expression of positive and negative regulators. In this issue of EMBO Reports, the Wilkinson lab uncovers a novel function of nonsense‐mediated RNA decay (NMD) in fine‐tuning the UPR [1]. NMD is an mRNA quality control mechanism known to destabilize aberrant mRNAs that contain premature termination codons. In this work, NMD was shown to determine the threshold of stress necessary to activate the UPR, in addition to adjusting the amplitude of downstream responses and the termination phase. These effects were mapped to the control of the mRNA stability of IRE1, a major ER stress transducer. This study highlights the dynamic crosstalk between mRNA metabolism and the proteostasis network demonstrating the physiological relevance of normal mRNA regulation by the NMD pathway.
See also: R Karam et al (May 2015)
In this issue of EMBO Reports, nonsense‐mediated RNA decay (NMD) is shown to fine‐tune the unfolded protein response (UPR). NMD determines the threshold of UPR activation, the amplitude of downstream responses and its termination.
- © 2015 The Authors
- The unfolded protein response is shaped by the NMD pathway
- Rachid Karam14,
- Chih‐Hong Lou1,
- Heike Kroeger2,
- Lulu Huang15,
- Jonathan H Lin2 and
- Miles F Wilkinson*,1,3
- 1Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
- 2Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- 3Institute of Genomic Medicine, University of California San Diego, La Jolla, CA, USA
- 4Ambry Genetics, Aliso Viejo, CA, USA
- 5 ISIS Pharmaceuticals, Carlsbad, CA, USA
- ↵*Corresponding author. Tel: +1 858 822 4819; E‐mail: mfwilkinson{at}ucsd.edu
The threshold for UPR triggering and its timely termination are shown to depend on the nonsense‐mediated RNA decay (NMD) pathway. NMD regulates the mRNAs of several UPR components, which underpins this effect.
Synopsis
This study shows that both the threshold for triggering the unfolded protein response (UPR) and its timely termination depend on the nonsense‐mediated RNA decay (NMD) pathway. The mRNAs of several UPR components are directly regulated through NMD, which underpins this effect.
UPR induction in response to innocuous stress is prevented by the NMD RNA decay pathway.
NMD is downregulated in response to bona fide stress to permit a maximal UPR response.
NMD acts by driving the rapid decay of several UPR component transcripts, including IRE1α mRNA.
NMD promotes timely UPR termination, thereby reducing the likelihood of stress‐induced apoptosis.
EMBO Reports (2015) 16: 599–609
- Received October 8, 2014.
- Revision received February 13, 2015.
- Accepted February 24, 2015.
- © 2015 The Authors
- Potent degradation of neuronal miRNAs induced by highly complementary targets
- Manuel de la Mata1,
- Dimos Gaidatzis1,2,
- Mirela Vitanescu15,
- Michael B Stadler1,2,3,
- Corinna Wentzel46,
- Peter Scheiffele4,
- Witold Filipowicz*,1,3 and
- Helge Großhans*,1
- 1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- 2Swiss Institute of Bioinformatics, Basel, Switzerland
- 3University of Basel, Basel, Switzerland
- 4Biozentrum, University of Basel, Basel, Switzerland
- 5Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland
- 6Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- ↵*
Corresponding author. Tel: +41 61 697 6993; E‐mail: witold.filipowicz{at}fmi.ch
Corresponding author. Tel: +41 61 697 6675; E‐mail: helge.grosshans{at}fmi.ch
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Synopsis
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Target‐induced non‐templated nucleotide addition (tailing) occurs on miRNAs, while they are bound to Argonaute.
TDMD and mRNA silencing are independent processes, permitting one target to induce degradation of several miRNA molecules.
mRNA silencing, but not TDMD, requires cooperativity among multiple target sites to reach high efficiency.
EMBO Reports (2015) 16: 500–511
- Received January 8, 2015.
- Revision received January 21, 2015.
- Accepted January 26, 2015.
- © 2015 The Authors
- IP3 signalling regulates exogenous RNAi in Caenorhabditis elegans
- Anikó I Nagy14†,
- Rafael P Vázquez‐Manrique2,3,†,
- Marie Lopez15,
- Christo P Christov1,
- María Dolores Sequedo2,3,
- Mareike Herzog16,
- Anna E Herlihy17,
- Maxime Bodak18,
- Roxani Gatsi19 and
- Howard A Baylis*,1
- 1Department of Zoology, University of Cambridge, Cambridge, UK
- 2Research Group in Molecular, Cellular and Genomic Biomedicine, Health Research Institute‐La Fe, Valencia, Spain
- 3Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain
- 4Heart and Vascular Centre, Semmelweis University, Budapest, Hungary
- 5 Unit Human Evolutionary Genetics, Institut Pasteur, Paris, France
- 6 Wellcome Trust Sanger Institute, Cambridge, UK
- 7 MRC Laboratory for Molecular Cell Biology, University College London, London, UK
- 8 ETH Zurich, Institute of Molecular Health Sciences, Zurich, Switzerland
- 9 Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide, Sevilla, Spain
- ↵*Corresponding author. Tel: +44 1223 336630; Fax: +44 1223 336676; E‐mail: hab28{at}cam.ac.uk
-
↵† These authors contributed equally to this work
Reducing intracellular IP3 signaling enhances RNAi sensitivity in C. elegans through a function of IP3 in the intestine. This suggests that an animal's physiology or environment may influence its RNAi responses.
Synopsis
Reducing intracellular IP3 signaling enhances RNAi sensitivity in C. elegans through a function of IP3 in the intestine. This suggests that an animal's physiology or environment may influence its RNAi responses.
Altering intracellular IP3 signalling modifies sensitivity to RNAi in different tissues.
Tissue‐specific rescue experiments suggest IP3 functions in the intestine to control RNAi sensitivity throughout the animal.
IP3 signalling mutations can further enhance the sensitivity of existing RNAi hypersensitive strains.
EMBO Reports (2015) 16: 341–350
- Received September 15, 2014.
- Revision received December 4, 2014.
- Accepted December 15, 2014.
- © 2015 The Authors
- The RNA‐binding protein Arrest (Bruno) regulates alternative splicing to enable myofibril maturation in Drosophila flight muscle
- Maria L Spletter1,
- Christiane Barz1,
- Assa Yeroslaviz1,
- Cornelia Schönbauer1,
- Irene R S Ferreira1,
- Mihail Sarov2,
- Daniel Gerlach34,
- Alexander Stark3,
- Bianca H Habermann1 and
- Frank Schnorrer*,1
- 1Max Planck Institute of Biochemistry, Martinsried, Germany
- 2Max Planck Institute of Cell Biology and Genetics, Dresden, Germany
- 3Research Institute of Molecular Pathology (IMP) Vienna Biocenter (VBC), Vienna, Austria
- 4Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
- ↵*Corresponding author. Tel: +49 89 8578 2434; E‐mail: schnorrer{at}biochem.mpg.de
Arrest (Bruno) regulates flight muscle‐specific splicing of a large number of genes encoding for sarcomeric proteins. Correct expression of these flight muscle‐specific isoforms is essential to build the contractile apparatus of fibrillar flight muscles.
Synopsis
Arrest (Bruno) regulates flight muscle‐specific splicing of a large number of genes encoding for sarcomeric proteins. Correct expression of these flight muscle‐specific isoforms is essential to build the contractile apparatus of fibrillar flight muscles.
Spalt major induces expression of the RNA binding protein Arrest in flight muscles.
Arrest induces fibrillar muscle‐specific splicing of sarcomeric protein isoforms in flight muscles.
Arrest is essential for normal myofibril maturation and sarcomere growth to prevent hyper‐contraction in adult flight muscles.
EMBO Reports (2015) 16: 178–191
- Received October 27, 2014.
- Revision received November 25, 2014.
- Accepted December 2, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- RNA‐processing proteins regulate Mec1/ATR activation by promoting generation of RPA‐coated ssDNA
- Nicola Manfrini1,
- Camilla Trovesi1,
- Maxime Wery2,
- Marina Martina1,
- Daniele Cesena1,
- Marc Descrimes2,
- Antonin Morillon*,2,
- Fabrizio d'Adda di Fagagna*,3,4 and
- Maria Pia Longhese*,1
- 1Dipartimento di Biotecnologie e Bioscienze, Università di Milano‐Bicocca, Milan, Italy
- 2Institut Curie, CNRS UMR3244 Université Pierre et Marie Curie, Paris Cedex 05, France
- 3IFOM Foundation‐FIRC Institute of Molecular Oncology Foundation, Milan, Italy
- 4Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- ↵*
Corresponding author. Tel: +33 156246570; Fax: +33 156246674; E‐mail: antonin.morillon{at}curie.fr
Corresponding author. Tel: +39 02574303227; Fax: +39 02574303231; E‐mail: fabrizio.dadda{at}ifom.eu
Corresponding author. Tel: +39 0264483425; Fax: +39 0264483565; E‐mail: mariapia.longhese{at}unimib.it
The S. cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 facilitate Mec1/ATR activation by promoting the formation of RPA‐coated ssDNA at dsDNA breaks.
Synopsis
The S. cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 facilitate Mec1/ATR activation by promoting the formation of RPA‐coated ssDNA at dsDNA breaks.
Xrn1 promotes the formation of single‐stranded DNA at the ends of double‐stranded DNA breaks.
Rrp6 and Trf4 contribute to the recruitment of RPA and Mec1/ATR to the single‐stranded DNA ends.
EMBO Reports (2015) 16: 221–231
- Received August 18, 2014.
- Revision received November 21, 2014.
- Accepted November 24, 2014.
- © 2014 The Authors
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