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484 results on '"Institute of Molecular Biology (IMB)"'

1. Dichotomy between the transcriptomic landscape of naturally versus accelerated aged murine hearts

Author: Monika Stoll, Anne-Sophie Armand, Leon J. De Windt, Thomas Thum, Martine de Boer, Federica De Majo, Blanche Schroen, Jana-Charlotte Hegenbarth, Dirk J. Duncker, Frank Rühle, Christian Bär, RS: FSE DMG, Cardiologie, RS: Carim - H05 Gene regulation, RS: Carim - H02 Cardiomyopathy, Biochemie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Cardiology, Maastricht University [Maastricht], Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Hannover Medical School [Hannover] (MHH), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), T.T. was supported by ERC Consolidator Grant LONGHEART, by ERA-CVD JCT2016 EXPERT and the DFG (TH903/22-1). C.B. was supported by the DFG (BA5631/2–1) and ERA-CVD JCT2016 EXPERT. D.J.D. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2011-ARENA and CVON2017-ARENA PRIME). A.S.A. was funded by Association Française contres les Myopathies (AFM 18802) L.D.W. and F.D.M. are supported by ERA-CVD JCT2016 EXPERT. L.D.W. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2017-ARENA PRIME). L.D.W. was further supported by ERC Consolidator Grant 311549 CALMIRS and a VICI award 918-156-47 from NWO. B.S. is supported by VIDI award 917.14.363 from NWO, Dekker grant 2014T105 from the Dutch Heart Foundation, further support comes from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2018 SHE-PREDICTS-HF), and a grant by the Health Foundation Limburg., Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Bodescot, Myriam
Subjects: 0301 basic medicine, Male, Aging, lcsh:Medicine, 030204 cardiovascular system & hematology, Gene regulatory networks, Transcriptome, Mice, 0302 clinical medicine, FAILURE, LONGEVITY, lcsh:Science, MUTATION, Telomere Shortening, Multidisciplinary, Aging, Premature, Heart, Telomere, CANCER, Cell biology, Mitochondria, PREDICTS, Antioxidant capacity, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, NUCLEAR ABNORMALITIES, Senescence, Premature aging, EXPRESSION, DNA repair, Biology, Article, Cardiac dysfunction, MECHANISMS, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Transcriptomics, Gene, Myocardium, lcsh:R, Proteins, 030104 developmental biology, DNA-DAMAGE, TELOMERE LENGTH, lcsh:Q, Ichthyosis, Lamellar
Abstract: We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.
Published: 2020

2. Antagonistic fungal enterotoxins intersect at multiple levels with host innate immune defences

Author: Xing Zhang, Dina Aggad, Damien Courtine, Jia-Xuan Chen, Nathalie Pujol, Benjamin W. Harding, Jonathan J. Ewbank, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), ANR-16-CE15-0001,ELEGINN,Analyse intégrée de l'immunité innée antifongique chez C. elegans(2016), ANR-16-CONV-0001,CENTURI,CenTuri : Centre Turing des Systèmes vivants(2016), pujol, nathalie, Analyse intégrée de l'immunité innée antifongique chez C. elegans - - ELEGINN2016 - ANR-16-CE15-0001 - AAPG2016 - VALID, CenTuri : Centre Turing des Systèmes vivants - - CENTURI2016 - ANR-16-CONV-0001 - CONV - VALID, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: Cancer Research, Nematoda, Gene Expression, QH426-470, Toxicology, Pathology and Laboratory Medicine, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Biological Coevolution, Enterotoxins, 0302 clinical medicine, Genes, Reporter, Gene expression, Medicine and Health Sciences, Toxins, Pathogen, Genetics (clinical), Caenorhabditis elegans, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Skin, Genetics, 0303 health sciences, Virulence, biology, Eukaryota, Animal Models, Spores, Fungal, STAT Transcription Factors, Experimental Organism Systems, Caenorhabditis Elegans, Host-Pathogen Interactions, Hypocreales, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pathogens, Anatomy, Integumentary System, Cellular Structures and Organelles, Research Article, Signal Transduction, Virulence Factors, Imaging Techniques, Toxic Agents, Bacterial Toxins, Green Fluorescent Proteins, Longevity, Research and Analysis Methods, Fungal Proteins, 03 medical and health sciences, Model Organisms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Fluorescence Imaging, Adults, Animals, Caenorhabditis elegans Proteins, Transport Vesicles, Molecular Biology, Transcription factor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Cell Nucleus, Innate immune system, Mechanism (biology), Host (biology), Organisms, Biology and Life Sciences, Nucleolus, Biological Transport, Cell Biology, biology.organism_classification, Invertebrates, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Immunity, Innate, Young Adults, Gene Expression Regulation, Age Groups, People and Places, Animal Studies, Caenorhabditis, Population Groupings, Epidermis, Zoology, 030217 neurology & neurosurgery, Antimicrobial Cationic Peptides
Abstract: Animals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system of Caenorhabditis elegans to dissect the action of two virulence factors from its natural fungal pathogen Drechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second increases STA-2 levels in the nucleus, modifies the nucleolus, and, potentially as a consequence of a host surveillance mechanism, causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens., Author summary When a pathogenic fungus invades an animal, it can deploy a bewildering battery of molecular weapons: hundreds of proteins are injected directly into the host’s cells to enable the fungus to grow and reproduce. We study a simple animal host, the nematode worm C. elegans and its natural enemy, the fungus Drechmeria coniospora, which has a large repertoire of uncharacterised potential “virulence factors”. Here, we focused on just two of these fungal proteins, called enterotoxins. By producing each enterotoxin inside the epidermis of C. elegans, we were able to study their specific effect on the host, and in particular on the way in which they altered the host’s immune defences. The two enterotoxins had strikingly different effects. One blocked the worms’ ability to make protective antimicrobial peptides, while the other actually stimulated their production. By combining genetics, biochemistry and cell biology, we uncovered the basis of these antagonistic actions. Each of the enterotoxins turned out to act by altering different aspects of the worms’ biology, despite both interfering with host protein translation. Our findings provide a first insight into the molecular and cellular basis of enterotoxins in this particular host-pathogen battle.
Published: 2021

3. Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence

Author: Brian Luke, Tina Wagner, Lara Pérez-Martínez, Félix Prado, René Schellhaas, Falk Butter, Merve Öztürk, Marta Barrientos-Moreno, [Wagner,T, Luke,B] Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany. [Pérez-Martínez,L, Schellhaas,R, Öztürk,M, Butter,F, Luke,B] Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany. [Barrientos-Moreno,M, Prado,F] Department of Genome Biology, Andalusian Molecular Biology and Regenerative Medicine Center (CABIMER), CSIC-University of Seville-University Pablo de Olavide, Seville, Spain., BL’s lab was supported by the Heisenberg Program of the Deutsche Forschungsgemeinschaft DFG - LU 1709/2-1. Research in FP’s lab was funded by grants from the Spanish government, Ministerio de Economía y Competitividad (BFU2015-63689-P)., Barrientos-Moreno, Marta, Öztürk, Merve, Prado, Félix, Butter, Falk, Luke, Brian, Barrientos-Moreno, Marta [0000-0002-2709-8437], Öztürk, Merve [0000-0003-2898-2176], Prado, Félix [0000-0001-9805-782X], Butter, Falk [0000-0002-7197-7279], and Luke, Brian [0000-0002-1648-5511]
Subjects: Telomerase, Protein Folding, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Rad52 DNA Repair and Recombination Protein [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Fungal Proteins::Saccharomyces cerevisiae Proteins [Medical Subject Headings], Gene Expression, Yeast and Fungal Models, Artificial Gene Amplification and Extension, QH426-470, Biochemistry, Polymerase Chain Reaction, Chromosome conformation capture, Histones, Cromatina, 0302 clinical medicine, Sirtuin 2, Macromolecular Structure Analysis, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Cellular Senescence, Organisms::Eukaryota::Fungi::Yeasts::Saccharomyces::Saccharomyces cerevisiae [Medical Subject Headings], 0303 health sciences, Chromosome Biology, Eukaryota, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Replication [Medical Subject Headings], Telomere, Subtelomere, Anatomy::Cells::Cellular Structures::Intracellular Space::Cell Nucleus::Cell Nucleus Structures::Intranuclear Space::Chromosomes::Chromosome Structures::Telomere [Medical Subject Headings], Chromatin, 3. Good health, Cell biology, Nucleic acids, Telomeres, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Division::Telomere Homeostasis [Medical Subject Headings], Experimental Organism Systems, Daño del ADN, Epigenetics, Research Article, Senescence, DNA Replication, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Amidohydrolases::Histone Deacetylases [Medical Subject Headings], Chromosome Structure and Function, Protein Structure, Saccharomyces cerevisiae Proteins, Saccharomyces cerevisiae, Biology, Research and Analysis Methods, Histone Deacetylases, Chromosomes, 03 medical and health sciences, Saccharomyces, Model Organisms, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::One-Carbon Group Transferases::Methyltransferases [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::Sirtuins::Sirtuin 2 [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Fungal Proteins::Saccharomyces cerevisiae Proteins::Silent Information Regulator Proteins, Saccharomyces cerevisiae [Medical Subject Headings], DNA-binding proteins, Genetics, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Recombinases::Rec A Recombinases::Rad51 Recombinase [Medical Subject Headings], Molecular Biology Techniques, Molecular Biology, 030304 developmental biology, Cromosomas, Senescencia celular, Organisms, Fungi, Biology and Life Sciences, Proteins, Telomere Homeostasis, Cell Biology, DNA, Methyltransferases, G2-M DNA damage checkpoint, Proteína recombinante y reparadora de ADN Rad52, Yeast, Rad52 DNA Repair and Recombination Protein, Repressor Proteins, Animal Studies, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::Repressor Proteins [Medical Subject Headings], DNA damage, Rad51 Recombinase, Homologous recombination, 030217 neurology & neurosurgery, Telómero, DNA Damage
Abstract: Telomeres have the ability to adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomere chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a distinct telomeric chromatin environment is a major requirement for the folding of yeast telomeres. We demonstrate that telomeres are not folded when cells enter replicative senescence, which occurs independently of short telomere length. Indeed, Sir2, Sin3 and Set2 protein levels are decreased during senescence and their absence may thereby prevent telomere folding. Additionally, we show that the homologous recombination machinery, including the Rad51 and Rad52 proteins, as well as the checkpoint component Rad53 are essential for establishing the telomere fold-back structure. This study outlines a method to interrogate telomere-subtelomere interactions at a single unmodified yeast telomere. Using this method, we provide insights into how the spatial arrangement of the chromosome end structure is established and demonstrate that telomere folding is compromised throughout replicative senescence., Author summary Telomeres are the protective caps of chromosome ends and prevent the activation of a local DNA damage response. In many organisms, telomeres engage in a loop-like structure which may provide an additional layer of end protection. As we still lack insight into the regulation of the folded telomere structure, we used budding yeast to develop a method to measure telomere folding and then study the genetic requirements for its establishment. We found that cells require the homologous recombination machinery as well as components of the DNA damage checkpoint to successfully establish a folded telomere. Through the deletion of telomerase in budding yeast, we investigated how telomere folding is regulated during replicative senescence, a process that occurs in the majority of telomerase negative human cells. During senescence, telomeres gradually shorten and erode until cells stop dividing which is a potent tumor suppressor and prevents unscheduled growth of potential cancer cells. We found, that the folded telomere structure is compromised as part of the cellular senescence response, but not due to telomere shortening per se. We think, that an altered telomeric chromatin environment during senescence is important to maintain an open state–which may be important for signaling or for repair.
Published: 2020

4. FRET-based dynamic structural biology: Challenges, perspectives and an appeal for open-science practices

Author: Lerner, Eitan, Barth, Anders, Hendrix, Jelle, Ambrose, Benjamin, Birkedal, Victoria, Blanchard, Scott C., Börner, Richard, Chung, Hoi Sung, Cordes, Thorben, Craggs, Timothy D., Deniz, Ashok A., Diao, Jiajia, Fei, Jingyi, Gonzalez, Ruben L., Gopich, Irina V., Ha, Taekjip, Hanke, Christian A., Haran, Gilad, Hatzakis, Nikos S., Hohng, Sungchul, Hong, Seok Cheol, Hugel, Thorsten, Ingargiola, Antonino, Joo, Chirlmin, Kapanidis, Achillefs N., Kim, Harold D., Laurence, Ted, Lee, Nam Ki, Lee, Tae Hee, Lemke, Edward A., Margeat, Emmanuel, Michaelis, Jens, Michalet, Xavier, Myong, Sua, Nettels, Daniel, Peulen, Thomas Otavio, Ploetz, Evelyn, Razvag, Yair, Robb, Nicole C., Schuler, Benjamin, Soleimaninejad, Hamid, Tang, Chun, Vafabakhsh, Reza, Lamb, Don C., Seidel, Claus A.M., Weiss, Shimon, Boudker, Olga, Institute of Chemistry, The Hebrew University of Jerusalem, The Hebrew University of Jerusalem (HUJ), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Hasselt University (UHasselt), University of Sheffield [Sheffield], Aarhus University [Aarhus], St Jude Children's Research Hospital, Hochschule Mittweida - University of Applied Sciences, National Institutes of Health [Bethesda] (NIH), Ludwig-Maximilians-Universität München (LMU), The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, University of Cincinnati (UC), University of Chicago, Columbia University [New York], Howard Hughes Medical Institute (HHMI), Weizmann Institute of Science [Rehovot, Israël], University of Copenhagen = Københavns Universitet (KU), Seoul National University [Seoul] (SNU), Korea University [Seoul], University of Freiburg [Freiburg], University of California [Los Angeles] (UCLA), University of California, Delft University of Technology (TU Delft), University of Oxford [Oxford], Georgia Institute of Technology [Atlanta], Lawrence Livermore National Laboratory (LLNL), Pennsylvania State University (Penn State), Penn State System, University Medical Center of the Johannes Gutenberg-University Mainz, Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Ulm (UUlm), Johns Hopkins University (JHU), Université de Zurich [Switzerland], University of California [San Francisco] (UCSF), University of Warwick [Coventry], University of Melbourne, Peking University [Beijing], Northwestern University [Evanston], The Scripps Research Institute [La Jolla, San Diego], University of Copenhagen = Københavns Universitet (UCPH), University of California (UC), University of Oxford, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), and Margeat, Emmanuel
Subjects: 0301 basic medicine, conformation, Open science, Computer science, Structural Biology and Molecular Biophysics, AMINOACYL-TRANSFER-RNA, INTRAMOLECULAR DISTANCE DISTRIBUTIONS, Review Article, RESONANCE ENERGY-TRANSFER, 01 natural sciences, biomolecules, FREELY DIFFUSING MOLECULES, Documentation, Fluorescence Resonance Energy Transfer, Mainstream, structural biology, Biology (General), General Neuroscience, NANO-POSITIONING SYSTEM, General Medicine, dynamics, INTRINSICALLY DISORDERED PROTEINS, Single Molecule Imaging, FLUORESCENCE CORRELATION SPECTROSCOPY, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Medicine, community, single-molecule, QH301-705.5, Science, Appeal, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Bioengineering, chemical biology, 010402 general chemistry, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, ALTERNATING-LASER EXCITATION, Biochemistry and Chemical Biology, molecular biophysics, biochemistry, Molecular Biology, Structure (mathematical logic), General Immunology and Microbiology, SINGLE-MOLECULE FRET, TRANSITION PATH TIMES, Data science, 0104 chemical sciences, 030104 developmental biology, FRET, Position paper, Generic health relevance, Biochemistry and Cell Biology
Abstract: International audience; Single-molecule FRET (smFRET) has become a mainstream technique for studying biomolecular structural dynamics. The rapid and wide adoption of smFRET experiments by an ever- increasing number of groups has generated significant progress in sample preparation, measurement procedures, data analysis, algorithms and documentation. Several labs that employ smFRET approaches have joined forces to inform the smFRET community about streamlining how to perform experiments and analyze results for obtaining quantitative information on biomolecular structure and dynamics. The recent efforts include blind tests to assess the accuracy and the precision of smFRET experiments among different labs using various procedures. These multi-lab studies have led to the development of smFRET procedures and documentation, which are important when submitting entries into the archiving system for integrative structure models, PDB- Dev. This position paper describes the current ‘state of the art’ from different perspectives, points to unresolved methodological issues for quantitative structural studies, provides a set of ‘soft recommendations’ about which an emerging consensus exists, and lists openly available resources for newcomers and seasoned practitioners. To make further progress, we strongly encourage‘open science’ practices.
Published: 2020

5. The 18S ribosomal <scp>RNA</scp> m 6 A methyltransferase Mettl5 is required for normal walking behavior in Drosophila

Author: Pablo Mier, Christof Niehrs, Ludivine Wacheul, Minh Anh Vu, Michael U. Musheev, Marc Graille, Mihika Pradhan, Jean-Yves Roignant, Miguel A. Andrade-Navarro, Mariangela Spagnuolo, Denis L. J. Lafontaine, Jessica Leismann, Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Fonds de la Recherche Nationale, Université Libre de Bruxelles, Charleroi-Gosselies, Belgium, Laboratoire de Biologie Structurale de la Cellule (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Division of Molecular Embryology - DKFZ-ZMBH Alliance, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), and ANR-16-CE11-0003,m6A,La modification m6A des ANRm: biogenèse et rôle dans la stabilité des ARNm(2016)
Subjects: Adenosine, Biochimie, m 6 A, Mettl5, Walking, Biology, Biochemistry, Ribosome, 18S ribosomal RNA, 03 medical and health sciences, 0302 clinical medicine, Gene expression, RNA, Ribosomal, 18S, Genetics, Animals, Humans, RNA methyltransferase, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, 030304 developmental biology, Behavior, 0303 health sciences, Messenger RNA, behavior, Biologie moléculaire, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Methyltransferases, m6A, Ribosomal RNA, Non-coding RNA, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 3. Good health, Cell biology, ribosome, RNA, Ribosomal, Drosophila, Biologie, 030217 neurology & neurosurgery, Small nuclear RNA, Reports
Abstract: RNA modifications have recently emerged as an important layer of gene regulation. N6-methyladenosine (m6A) is the most prominent modification on eukaryotic messenger RNA and has also been found on noncoding RNA, including ribosomal and small nuclear RNA. Recently, several m6A methyltransferases were identified, uncovering the specificity of m6A deposition by structurally distinct enzymes. In order to discover additional m6A enzymes, we performed an RNAi screen to deplete annotated orthologs of human methyltransferase-like proteins (METTLs) in Drosophila cells and identified CG9666, the ortholog of human METTL5. We show that CG9666 is required for specific deposition of m6A on 18S ribosomal RNA via direct interaction with the Drosophila ortholog of human TRMT112, CG12975. Depletion of CG9666 yields a subsequent loss of the 18S rRNA m6A modification, which lies in the vicinity of the ribosome decoding center; however, this does not compromise rRNA maturation. Instead, a loss of CG9666-mediated m6A impacts fly behavior, providing an underlying molecular mechanism for the reported human phenotype in intellectual disability. Thus, our work expands the repertoire of m6A methyltransferases, demonstrates the specialization of these enzymes, and further addresses the significance of ribosomal RNA modifications in gene expression and animal behavior., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

6. tRNA 2'-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila

Author: Jean-Yves Roignant, Margarita T Angelova, Vincent Guérineau, Caroline Jacquier, Clément Carré, Bruno Da Silva, Christophe Antoniewski, Matthias Schaefer, Souraya Khouider, Mira Brazane, Yuri Motorin, Salman Shehzada, Damien Brégeon, Tina Lence, Virginie Marchand, Valérie Bourguignon-Igel, Dilyana G. Dimitrova, Cyrinne Achour, Catherine Goyenvalle, Laure Teysset, Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), and Medizinische Universität Wien = Medical University of Vienna
Subjects: Small RNA, Saccharomyces cerevisiae Proteins, Animals, Drosophila melanogaster/genetics, Gene Expression Regulation/genetics, Gene Silencing, Humans, Methylation, Methyltransferases/genetics, Nuclear Proteins/genetics, RNA Interference, RNA, Transfer/genetics, Saccharomyces cerevisiae/genetics, Saccharomyces cerevisiae Proteins/genetics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, tRNA Methyltransferases/genetics, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, RNA, Transfer, RNA interference, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Gene, 030304 developmental biology, 0303 health sciences, tRNA Methyltransferases, 2'-O-methylation, Nucleic Acid Enzymes, 030302 biochemistry & molecular biology, RNA, Nuclear Proteins, Translation (biology), [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Methyltransferases, Cell biology, RNA silencing, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Drosophila melanogaster, Gene Expression Regulation, Transfer RNA
Abstract: 2′-O-Methylation (Nm) represents one of the most common RNA modifications. Nm affects RNA structure and function with crucial roles in various RNA-mediated processes ranging from RNA silencing, translation, self versus non-self recognition to viral defense mechanisms. Here, we identify two Nm methyltransferases (Nm-MTases) in Drosophila melanogaster (CG7009 and CG5220) as functional orthologs of yeast TRM7 and human FTSJ1. Genetic knockout studies together with MALDI-TOF mass spectrometry and RiboMethSeq mapping revealed that CG7009 is responsible for methylating the wobble position in tRNAPhe, tRNATrp and tRNALeu, while CG5220 methylates position C32 in the same tRNAs and also targets additional tRNAs. CG7009 or CG5220 mutant animals were viable and fertile but exhibited various phenotypes such as lifespan reduction, small RNA pathways dysfunction and increased sensitivity to RNA virus infections. Our results provide the first detailed characterization of two TRM7 family members in Drosophila and uncover a molecular link between enzymes catalyzing Nm at specific tRNAs and small RNA-induced gene silencing pathways.
Published: 2020

7. Proteome-wide identification of NEDD8 modification sites reveals distinct proteomes for canonical and atypical NEDDylation

Author: Sofia Lobato-Gil, Jan B. Heidelberger, Petra Beli, Chantal Maghames, Manuel S. Rodriguez, Lorene Brunello, Aymeric P. Bailly, Dimitris P. Xirodimas, Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ATIP/Avenir fellowship award, Emmy Noether Program (BE 5342/1-1), German Research Foundation award SFB1177, Occitanie region, France - Prematuration program Ubipièges award, ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz (JGU), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: 0301 basic medicine, NEDD8-SUMO polymers, Spliceosome, NEDD8 Protein, Proteome, diGly signatures, NEDD8, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, Catalytic Domain, Endopeptidases, Hybrid chains, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, biology, Chemistry, DNA replication, HCT116 Cells, mRNA surveillance, Canonical, Cell biology, 030104 developmental biology, Proteasome, biology.protein, Small Ubiquitin-Related Modifier Proteins, Neddylation, NEDP1, Proteotoxic stress, 030217 neurology & neurosurgery, Atypical, Nucleolus-related inclusions, Cell Nucleolus
Abstract: International audience; The ubiquitin-like molecule NEDD8 controls several biological processes and is a promising target for therapeutic intervention. NEDDylation occurs through specific NEDD8 enzymes (canonical) or enzymes of the ubiquitin system (atypical). Identification of NEDD8 sites on substrates is critical for delineating the processes controlled by NEDDylation. By combining the use of the NEDD8 R74K mutant with anti-di-glycine (anti-diGly) antibodies, we identified 1,101 unique NEDDylation sites in 620 proteins. Bioinformatics analysis reveals that canonical and atypical NEDDylation have distinct proteomes; the spliceosome/mRNA surveillance/DNA replication and ribosome/proteasome, respectively. The data also reveal the formation of poly-NEDD8, hybrid NEDD8-ubiquitin, and NEDD8-SUMO-2 chains as potential molecular signals. In particular, NEDD8-SUMO-2 chains are induced upon proteotoxic stress (atypical) through NEDDylation of K11 in SUMO-2, and conjugates accumulate in previously described nucleolus-related inclusions. The study uncovers a diverse proteome for NEDDylation and is consistent with the concept of extensive cross-talk between ubiquitin and Ubls under proteotoxic stress conditions.
Published: 2020

8. NOseq: amplicon sequencing evaluation method for RNA m6A sites after chemical deamination

Author: Jean-Yves Roignant, Maksim V. Sednev, Andreas Hildebrandt, Tina Lence, Florian Pichot, Mark Helm, Aurellia Galliot, Virginie Marchand, Thomas Kemmer, Julian König, Yuri Motorin, Claudia Höbartner, Stephan Werner, GONNET, JULIE, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Würzburg, Institute of Molecular Biology (IMB), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz (JGU), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lausanne (UNIL)-Université de Lausanne (UNIL)
Subjects: Adenosine, Sequence analysis, AcademicSubjects/SCI00010, Bisulfite sequencing, Deamination, Adenosine/analogs & derivatives, Adenosine/analysis, Algorithms, Animals, Chromatography, Liquid, Drosophila melanogaster/genetics, HEK293 Cells, HeLa Cells, High-Throughput Nucleotide Sequencing/methods, Humans, RNA/chemistry, RNA, Long Noncoding/chemistry, RNA, Messenger/chemistry, RNA, Ribosomal, 18S/chemistry, Sequence Alignment, Sequence Analysis, RNA/methods, Tandem Mass Spectrometry, Sequence alignment, Computational biology, Biology, 010402 general chemistry, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 01 natural sciences, Transcriptome, 03 medical and health sciences, Narese/13, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, RNA, Ribosomal, 18S, RNA, Messenger, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Sequence Analysis, RNA, RNA, High-Throughput Nucleotide Sequencing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Amplicon, Ribosomal RNA, 0104 chemical sciences, Drosophila melanogaster, Methods Online, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA, Long Noncoding
Abstract: Methods for the detection of m6A by RNA-Seq technologies are increasingly sought after. We here present NOseq, a method to detect m6A residues in defined amplicons by virtue of their resistance to chemical deamination, effected by nitrous acid. Partial deamination in NOseq affects all exocyclic amino groups present in nucleobases and thus also changes sequence information. The method uses a mapping algorithm specifically adapted to the sequence degeneration caused by deamination events. Thus, m6A sites with partial modification levels of ∼50% were detected in defined amplicons, and this threshold can be lowered to ∼10% by combination with m6A immunoprecipitation. NOseq faithfully detected known m6A sites in human rRNA, and the long non-coding RNA MALAT1, and positively validated several m6A candidate sites, drawn from miCLIP data with an m6A antibody, in the transcriptome of Drosophila melanogaster. Conceptually related to bisulfite sequencing, NOseq presents a novel amplicon-based sequencing approach for the validation of m6A sites in defined sequences.
Published: 2020

9. tRNA 2’-O-methylation modulates small RNA silencing and life span in Drosophila

Author: Matthias Schaefer, Margarita T Angelova, Caroline Jacquier, Valérie Bourguignon-Igel, Tina Lence, Yuri Motorin, Vincent Guérineau, Damien Brégeon, Virginie Marchand, Dilyana G. Dimitrova, Clément Carré, Bruno Da Silva, Cyrinne Achour, Christophe Antoniewski, Salman Shehzada, Catherine Goyenvalle, Laure Teysset, Jean-Yves Roignant, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'automatique et de génie des procédés (LAGEP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), Bioinformatique [IBPS] (IBPS-Artbio), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Small RNA, 2'-O-methylation, [SDV]Life Sciences [q-bio], RNA, Translation (biology), Wobble base pair, Biology, Cell biology, 03 medical and health sciences, RNA silencing, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Transfer RNA, Gene silencing, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: 2’-O-methylation (Nm) represents one of the most common RNA modifications. Nm affects RNA structure and function with crucial roles in various RNA-mediated processes ranging from RNA silencing, translation, self versus non-self recognition to viral defense mechanisms. Here, we identify two novel Nm methyltransferases (Nm-MTases) in Drosophila melanogaster (CG7009 and CG5220) as functional orthologs of yeast TRM7 and human FTSJ1, respectively. Genetic knockout studies together with MALDI-TOF mass spectrometry and RiboMethSeq mapping revealed that CG7009 is responsible for methylating the wobble position in tRNAPhe, tRNATrp and tRNALeu, while subsequently, CG5220 methylates position C32 in the same tRNAs and targets also additional tRNAs. CG7009 or CG5220 mutant animals were viable and fertile but exhibited various phenotypes such as life span reduction, small RNA pathways dysfunction and increased sensitivity to RNA virus infections. Our results provide the first detailed characterization of two TRM7 family members in Drosophila and uncover a molecular link between enzymes catalysing Nm at specific tRNAs and small RNA-induced gene silencing pathways.
Published: 2019

10. Absolute quantification of noncoding RNA by microscale thermophoresis

Author: Raffael Schaffrath, Yuri Motorin, Kathrin Thüring, Mark Helm, Michael Stock, Roland Klassen, Akif Ciftci, Virginie Marchand, Sebastian A. Leidel, Jean-Yves Roignant, Aurellia Galliot, Adeline Galvanin, Karin Scharmann, Dominik Jacob, Johannes Gutenberg - Universität Mainz (JGU), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Freiburg [Freiburg], Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Institute of Molecular Biology (IMB), and Universität Kassel [Kassel]
Subjects: tRNA stability, RNA, Untranslated, Absolute quantification, RNA Quantification | Hot Paper, Computational biology, 010402 general chemistry, 01 natural sciences, Catalysis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA modification, 540 Chemistry, hybridization, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Chemistry, Microscale thermophoresis, Communication, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Ribosomal RNA, Non-coding RNA, microscale thermophoresis, Communications, 0104 chemical sciences, Tissue Differentiation, Transfer RNA, 570 Life sciences, biology, fluorescence, RNA quantification
Abstract: Accurate quantification of the copy numbers of noncoding RNA has recently emerged as an urgent problem, with impact on fields such as RNA modification research, tissue differentiation, and others. Herein, we present a hybridization‐based approach that uses microscale thermophoresis (MST) as a very fast and highly precise readout to quantify, for example, single tRNA species with a turnaround time of about one hour. We developed MST to quantify the effect of tRNA toxins and of heat stress and RNA modification on single tRNA species. A comparative analysis also revealed significant differences to RNA‐Seq‐based quantification approaches, strongly suggesting a bias due to tRNA modifications in the latter. Further applications include the quantification of rRNA as well as of polyA levels in cellular RNA.
Published: 2019

11. A subtelomeric region affects telomerase-negative replicative senescence in Saccharomyces cerevisiae

Author: Stephan Eberhard, Pascale Jolivet, Maria Teresa Teixeira, Kamar Serhal, Zhou Xu, Brian Luke, Marco Graf, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (LBMCE), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), Physiologie membranaire et moléculaire du chloroplaste (PMMC), Sorbonne Université (SU)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Xu, Zhou, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: 0301 basic medicine, Senescence, Telomerase, Saccharomyces cerevisiae Proteins, DNA repair, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, lcsh:Medicine, Context (language use), Biology, Article, 03 medical and health sciences, 0302 clinical medicine, lcsh:Science, Cellular Senescence, Telomere Shortening, Multidisciplinary, lcsh:R, Cell Cycle, Recombinational DNA Repair, Telomere, biology.organism_classification, Subtelomere, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Chromosome Structures, Essential gene, lcsh:Q, 030217 neurology & neurosurgery, Cell Division
Abstract: In eukaryotes, telomeres determine cell proliferation potential by triggering replicative senescence in the absence of telomerase. In Saccharomyces cerevisiae, senescence is mainly dictated by the first telomere that reaches a critically short length, activating a DNA-damage-like response. How the corresponding signaling is modulated by the telomeric structure and context is largely unknown. Here we investigated how subtelomeric elements of the shortest telomere in a telomerase-negative cell influence the onset of senescence. We found that a 15 kb truncation of the 7L subtelomere widely used in studies of telomere biology affects cell growth when combined with telomerase inactivation. This effect is likely not explained by (i) elimination of sequence homology at chromosome ends that would compromise homology-directed DNA repair mechanisms; (ii) elimination of the conserved subtelomeric X-element; (iii) elimination of a gene that would become essential in the absence of telomerase; and (iv) heterochromatinization of inner genes, causing the silencing of an essential gene in replicative senescent cells. This works contributes to better delineate subtelomere functions and their impact on telomere biology.
Published: 2018

12. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells

Author: Stephen P. Jackson, Mareike Herzog, Alejandra Bruna, Luca Pellegrini, Violeta Serra, Mark J. O'Connor, Zhongwu Lai, Chloé Lescale, Jacqueline J.L. Jacobs, Fengtang Yang, Jonathan Lam, Matylda Sczaniecka-Clift, Abigail Shea, Carlos Caldas, Matthias Ostermaier, Gabriel Balmus, Julia Coates, Wenming Wei, Inge de Krijger, Yaron Galanty, Mukerrem Demir, Ludovic Deriano, Petra Beli, Domenic Pilger, Harveer Dev, Rimma Belotserkovskaya, Alistair Martin, Beiyuan Fu, Ting-Wei Will Chiang, Qian Wu, Dev, Harveer [0000-0003-2874-6894], Yang, Fengtang [0000-0002-3573-2354], Balmus, Gabriel [0000-0003-2872-4468], Serra, Violeta [0000-0001-6620-1065], Beli, Petra [0000-0001-9507-9820], Pellegrini, Luca [0000-0002-9300-497X], Deriano, Ludovic [0000-0002-9673-9525], Jacobs, Jacqueline JL [0000-0002-7704-4795], Jackson, Stephen P [0000-0001-9317-7937], Apollo - University of Cambridge Repository, Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge [UK] (CAM), Department of Biochemistry [Cambridge], Cambridge University Hospitals - NHS (CUH), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Wellcome Trust Sanger Institute [Hinxton, UK], AstraZeneca US [Waltham, USA], AstraZeneca [Cambridge, UK], The Wellcome Trust Sanger Institute [Cambridge], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], The SPJ lab is largely funded by a Cancer Research UK (CRUK) Program Grant, C6/A18796, and a Wellcome Trust (WT) Investigator Award, 206388/Z/17/Z. Core infrastructure funding was provided by CRUK grant C6946/A24843 and WT grant WT203144. S.P.J. receives a salary from the University of Cambridge. H.D. is funded by WT Clinical Fellowship 206721/Z/17/Z. TWC was supported by a Cambridge International Scholarship. D.P. is funded by Cancer Research UK studentship C6/A21454. The P.B. lab is supported by the Emmy Noether Program (BE 5342/1-1) from the German Research Foundation and a Marie Curie Career Integration Grant from the European Commission (630763). The L.P. lab is funded by the WT (investigator award 104641/Z/14/Z) and the Medical Research Council (project grant MR/N000161/1). The C.C. lab was supported with funding from CRUK. The J.J. lab was supported by the European Research Council grant ERC-StG 311565, The Dutch Cancer Society (KWF) grant KWF 10999, and the Netherlands Organization for Scientific Research (NWO) as part of the National Roadmap Large-scale Research Facilities of the Netherlands, Proteins@Work (project no. 184.032.201 to the Proteomics Facility of the Netherlands Cancer Institute). The L.D. lab is funded by the Institut Pasteur, the Institut National du Cancer (no. PLBIO16-181) and the European Research Council (starting grant agreement no. 310917). W.W. is part of the Pasteur–Paris University (PPU) International PhD program and this project received funding from the CNBG company, China. Q.W. is funded by the Wellcome Trust (200814/Z/16/Z ). The V.S. lab work was funded by the Instituto de Salud Carlos III (ISCIII), an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI17-01080 to VS), the European Research Area-NET, Transcan-2 (AC15/00063), a non-commercial research agreement with AstraZeneca UK, and structural funds from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 540) and the Orozco Family. V.S. received a salary and travel support to C.C.’s lab from ISCIII (CP14/00228, MV15/00041) and the FERO Foundation., The authors thank all S.P.J. laboratory members for support and advice, and Cambridge colleagues N. Lawrence for OMX super-resolution microscopy support and R. Butler for help with computational image analyses and programming. The authors also thank S. Selivanova and S. Hough for help with plasmid amplification, sample preparation and tissue culture maintenance, K. Dry for extensive editorial assistance, F. Muñoz-Martinez for assistance with CRISPR–Cas9 knockout generation, L. Radu for assistance with protein purification, C. Lord (Institute of Cancer Research, London) for SUM149PT cells, D. Durocher (University of Toronto, Canada) for U2OS LacSceIII cells, F. Alt (Harvard University, USA) for CH12F3 cells and 53bp1 knockout CH12F3 cell clones, T. Honjo (Kyoto University, Japan) for permission to use the CH12F3 cell line, and J. Serrat in the Jacobs lab for technical assistance, Institut Pasteur [Paris], and Johannes Gutenberg - Universität Mainz (JGU)
Subjects: MESH: DNA Breaks, Double-Stranded, RAD51, Cell Cycle Proteins, Poly (ADP-Ribose) Polymerase Inhibitor, MESH: Recombinational DNA Repair, Mice, MESH: Animals, DNA Breaks, Double-Stranded, skin and connective tissue diseases, Cancer, Telomere-binding protein, Ovarian Neoplasms, MESH: Breast Neoplasms / metabolism, MESH: Telomere-Binding Proteins / metabolism, 3. Good health, Cell biology, MESH: HEK293 Cells, MESH: Proteins / genetics, MESH: Telomere-Binding Proteins / genetics, MESH: Tumor Suppressor p53-Binding Protein 1 / metabolism, MESH: Xenograft Model Antitumor Assays, Telomere-Binding Proteins, MESH: Ovarian Neoplasms / drug therapy, Bone Neoplasms, MESH: Ovarian Neoplasms / metabolism, Article, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Bone Neoplasms / metabolism, Humans, MESH: Osteosarcoma / metabolism, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Tumor Suppressor p53-Binding Protein 1 / genetics, Dose-Response Relationship, Drug, HEK 293 cells, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, MESH: BRCA1 Protein / deficiency, 030104 developmental biology, Multiprotein Complexes, MESH: Mad2 Proteins / metabolism, MESH: Breast Neoplasms / genetics, MESH: Bone Neoplasms / drug therapy, Cisplatin, Homologous recombination, MESH: Osteosarcoma / genetics, MESH: Female, 0301 basic medicine, DNA End-Joining Repair, MESH: Proteins / metabolism, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Osteosarcoma / pathology, MESH: Breast Neoplasms / pathology, Homologous Recombination, Polymerase, MESH: Breast Neoplasms / drug therapy, Osteosarcoma, biology, Chemistry, BRCA1 Protein, DNA damage and repair, MESH: Poly(ADP-ribose) Polymerase Inhibitors / pharmacology, MESH: Bone Neoplasms / genetics, DNA-Binding Proteins, MESH: Bone Neoplasms / pathology, Mad2 Proteins, Female, MESH: Ovarian Neoplasms / genetics, Tumor Suppressor p53-Binding Protein 1, MESH: Cisplatin / pharmacology, MESH: Cell Line, Tumor, Lymphocytes, Null, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: BRCA1 Protein / genetics, Poly(ADP-ribose) Polymerase Inhibitors, Cell Line, Tumor, MESH: Drug Resistance, Neoplasm* / genetics, MESH: Mad2 Proteins / genetics, MESH: Ovarian Neoplasms / pathology, Animals, MESH: Mice, MESH: Osteosarcoma / drug therapy, Oligonucleotide, Protective Devices, Recombinational DNA Repair, Cell Biology, MESH: Multiprotein Complexes, Xenograft Model Antitumor Assays, HEK293 Cells, Drug Resistance, Neoplasm, biology.protein, MESH: DNA End-Joining Repair, MESH: DNA-Binding Proteins
Abstract: International audience; BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
Published: 2018

13. A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure

Author: Mohamed G. Atta, Victor Duarte, Yuri Motorin, Roman-Ulrich Müller, Falk Butter, Christoph Dieterich, Anja Freiwald, Stephan Werner, Annika Kotter, Christina Dal Magro, Mark Helm, Patrick Keller, Michael Ignarski, Virginie Marchand, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University Hospital of Cologne [Cologne], Institute of Molecular Biology (IMB), Universität Heidelberg [Heidelberg] = Heidelberg University, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz (JGU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Universität Heidelberg [Heidelberg]
Subjects: 0301 basic medicine, Stereochemistry, Thioacetal, 010402 general chemistry, 01 natural sciences, Catalysis, Nucleobase, isotope labelling, 03 medical and health sciences, chemistry.chemical_compound, Acetals, RNA modifications, Tandem Mass Spectrometry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Ribose, Escherichia coli, Moiety, Sulfhydryl Compounds, chemistry.chemical_classification, Chemistry, thioacetals, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, radical-SAM enzymes, Chemical space, 0104 chemical sciences, LC-MS, RNA, Bacterial, 030104 developmental biology, Enzyme, Nucleic Acid Conformation, Hydrogen–deuterium exchange, Chromatography, Liquid
Abstract: International audience; Recently discovered new chemical entities in RNA modifications have involved surprising functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over 100 signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds that are new structures of RNA modifications. One structure was elucidated by deuterium exchange and high-resolution mass spectrometry. The structure of msms2 i6 A (2-methylthiomethylenethio-N6-isopentenyl-adenosine) was confirmed by methione-D3 feeding experiments and by synthesis of the nucleobase. The msms2 i6 A contains a thioacetal, shown in vitro to be biosynthetically derived from ms2 i6 A by the radical-SAM enzyme MiaB. This enzyme performs thiomethylation, forming ms2 i6 A from i6 A in a first turnover. The new thioacetal is formed by a second turnover. Along with the pool of 36 new modifications, this work describes a new layer of RNA modification chemistry.
Published: 2018

14. The Emerging Field of Epitranscriptomics in Neurodevelopmental and Neuronal Disorders

Author: Jean-Yves Roignant, Nadja Dinges, Tina Lence, Clément Carré, Dilyana G. Dimitrova, Margarita T Angelova, Lina Worpenberg, Teysset, Laure, Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: 0301 basic medicine, Histology, lcsh:Biotechnology, Biomedical Engineering, neurons, Bioengineering, Review, Biology, 03 medical and health sciences, [SCCO]Cognitive science, lcsh:TP248.13-248.65, Epitranscriptomics, Gene expression, m5C, Regulation of gene expression, disease, Bioengineering and Biotechnology, RNA, Translation (biology), m6A, [SCCO] Cognitive science, RNA modification, Nm, Cell biology, 030104 developmental biology, Histone, Transfer RNA, biology.protein, Human genome, pseudouridine, Biotechnology
Abstract: International audience; Analogous to DNA methylation and histone modifications, RNA modifications represent a novel layer of regulation of gene expression. The dynamic nature and increasing number of RNA modifications offer new possibilities to rapidly alter gene expression upon specific environmental changes. Recent lines of evidence indicate that modified RNA molecules and associated complexes regulating and "reading" RNA modifications play key roles in the nervous system of several organisms, controlling both, its development and function. Mutations in several human genes that modify transfer RNA (tRNA) have been linked to neurological disorders, in particular to intellectual disability. Loss of RNA modifications alters the stability of tRNA, resulting in reduced translation efficiency and generation of tRNA fragments, which can interfere with neuronal functions. Modifications present on messenger RNAs (mRNAs) also play important roles during brain development. They contribute to neuronal growth and regeneration as well as to the local regulation of synaptic functions. Hence, potential combinatorial effects of RNA modifications on different classes of RNA may represent a novel code to dynamically fine tune gene expression during brain function. Here we discuss the recent findings demonstrating the impact of modified RNAs on neuronal processes and disorders.
Published: 2018

15. The Linker Histone GH1-HMGA1 Is Involved in Telomere Stability and DNA Damage Repair

Author: Fatiha Benyahya, Falk Butter, Cyril Charbonnel, Oleh Rymarenko, Olivier Da Ines, Charles I. White, Simon Amiard, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB), Region Auvergne 105060, Centre National de la Recherche Scientifique, Universite Clermont Auvergne, Institut National de la Sante et la Recherche Medicale, Rhineland Palatinate Forschungsschwerpunkt Gene Regulation in Evolution and Development (GeneRED), Deutsche Forschungsgemeinschaft BU 2996/1, Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), and White, Charles
Subjects: 0301 basic medicine, DNA, Bacterial, DNA Repair, Physiology, Telomere-Binding Proteins, Arabidopsis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Plant Science, Fluorescence, Histones, 03 medical and health sciences, Telomere Homeostasis, Genetics, Arabidopsis thaliana, Homologous Recombination, Telomerase, HMGA Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Arabidopsis Proteins, HMGA, Articles, Telomere, biology.organism_classification, Chromatin, Cell biology, 030104 developmental biology, High-mobility group, Histone, Mutation, biology.protein, Homologous recombination, DNA Damage, Protein Binding
Abstract: International audience; Despite intensive searches, few proteins involved in telomere homeostasis have been identified in plants. Here, we used pull-down assays to identify potential telomeric interactors in the model plant species Arabidopsis (Arabidopsis thaliana). We identified the candidate protein GH1-HMGA1 (also known as HON4), an uncharacterized linker histone protein of the High Mobility Group Protein A (HMGA) family in plants. HMGAs are architectural transcription factors and have been suggested to function in DNA damage repair, but their precise biological roles remain unclear. Here, we show that GH1-HMGA1 is required for efficient DNA damage repair and telomere integrity in Arabidopsis. GH1-HMGA1 mutants exhibit developmental and growth defects, accompanied by ploidy defects, increased telomere dysfunction-induced foci, mitotic anaphase bridges, and degraded telomeres. Furthermore, mutants have a higher sensitivity to genotoxic agents such as mitomycin C and γ-irradiation. Our work also suggests that GH1-HMGA1 is involved directly in the repair process by allowing the completion of homologous recombination.
Published: 2017

16. Exploring Quantitative Yeast Phenomics with Single-Cell Analysis of DNA Damage Foci

Author: Brian Luke, Marco Graf, Matej Usaj, Elizabeth N. Koch, Adrian J. Verster, Tina L. Sing, Dogus Murat Altintas, Zhaolei Zhang, Brenda J. Andrews, Virginie Ribaud, Michael Costanzo, Jacques Rougemont, Charles Boone, David Shore, Grant W. Brown, Robi D. Mitra, Erin B. Styles, Cyril Ribeyre, Daniele Novarina, Marco Muzi-Falconi, Lee Zamparo, Karen Founk, David Mayhew, Chad L. Myers, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de Microbiologie et Médecine Moléculaire, Faculté de Médecine, Université de Genève (UNIGE), Bioinformatics and Biostatistics Core Facility [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), McMaster University, Banting and Best Department of Medical Research, and University of Toronto
Subjects: 0301 basic medicine, Histology, Saccharomyces cerevisiae Proteins, DNA Repair, DNA damage, DNA repair, Saccharomyces cerevisiae, Computational biology, Genome, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Single-cell analysis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Genetics, biology, RecQ Helicases, Helicase, Membrane Proteins, Cell Biology, biology.organism_classification, Rad52 DNA Repair and Recombination Protein, 030104 developmental biology, biology.protein, Functional genomics, Sgs1, DNA Damage
Abstract: A significant challenge of functional genomics is to develop methods for genome-scale acquisition and analysis of cell biological data. Here, we present an integrated method that combines genome-wide genetic perturbation of Saccharomyces cerevisiae with high-content screening to facilitate the genetic description of sub-cellular structures and compartment morphology. As proof of principle, we used a Rad52-GFP marker to examine DNA damage foci in ∼20 million single cells from ∼5,000 different mutant backgrounds in the context of selected genetic or chemical perturbations. Phenotypes were classified using a machine learning-based automated image analysis pipeline. 345 mutants were identified that had elevated numbers of DNA damage foci, almost half of which were identified only in sensitized backgrounds. Subsequent analysis of Vid22, a protein implicated in the DNA damage response, revealed that it acts together with the Sgs1 helicase at sites of DNA damage and preferentially binds G-quadruplex regions of the genome. This approach is extensible to numerous other cell biological markers and experimental systems.
Published: 2016

17. Nitrate signaling: adaptation to fluctuating environments

Author: Yi-Fang Tsay, Nigel M. Crawford, Gloria M. Coruzzi, Gabriel Krouk, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Cell and Developmental Biology [San Diego], Division of Biological Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California-University of California [San Diego] (UC San Diego), University of California-University of California, Center for Genomics and Systems Biology, Department of Biology [New York], New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: 0106 biological sciences, Nitrogen assimilation, Systems biology, Gene regulatory network, Plant Science, Biology, 01 natural sciences, Nitrate pollution, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, NO3, Nitrate, Gene Expression Regulation, Plant, Gene Regulatory Networks, nitrate transport, Nitarte regulation, nitrate uptake, Plant Proteins, 030304 developmental biology, nitrate assimilation, 0303 health sciences, Nitrates, Ecology, Gene Expression Profiling, Assimilation (biology), Plants, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Adaptation, Physiological, chemistry, 13. Climate action, Nitrate transport, Protein Kinases, Signal Transduction, Transcription Factors, 010606 plant biology & botany
Abstract: Nitrate (NO(3)(-)) is a key nutrient as well as a signaling molecule that impacts both metabolism and development of plants. Understanding the complexity of the regulatory networks that control nitrate uptake, metabolism, and associated responses has the potential to provide solutions that address the major issues of nitrate pollution and toxicity that threaten agricultural and ecological sustainability and human health. Recently, major advances have been made in cataloguing the nitrate transcriptome and in identifying key components that mediate nitrate signaling. In this perspective, we describe the genes involved in nitrate regulation and how they influence nitrate transport and assimilation, and we discuss the role of systems biology approaches in elucidating the gene networks involved in NO(3)(-) signaling adaptation to fluctuating environments.
Published: 2010

18. Exposures of zebrafish through diet to three environmentally relevant mixtures of PAHs produce behavioral disruptions in unexposed F1 and F2 descendant

Author: Caroline Vignet, François Brion, Bon Chu Chung, Manon Goubeau, Hélène Budzinski, Olivier Kah, Lucette Joassard, Tiphaine Guionnet, Marie-Laure Bégout, Xavier Cousin, Karyn Le Menach, Laura Lyphout, Laboratoire d'ecotoxicologie, Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Laboratoire des Ressources Halieutiques (IFREMER), Département Systèmes Sous-Marins - IFREMER, Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This study was supported financially by the ANR project ConPhyPoP (CES 09_002) and CPER A2E. This later project is co-financed by the European Union with the European fund of regional development. A doctoral grant was received from the Région Poitou-Charentes and froml’Institut Français de Recherche pour l’Exploitation de la Mer (C.V.). This work was part of the LABEX COTE cluster of excellence 'Continental to coastal ecosystems'., Laboratoire d'Écotoxicologie (LEX), Biogéochimie et Ecotoxicologie (BE), Laboratoire Ressources halieutiques Boulogne sur mer (LRHBL), Halieutique Manche Mer du Nord (HMMN), Environnements et Paléoenvironnements OCéaniques (EPOC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA), Lecoupe-Grainville, Marie, and Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)
Subjects: Health, Toxicology and Mutagenesis, Polycyclic aromatic hydrocarbon, 010501 environmental sciences, Anxiety, Endocrine Disruptors, 01 natural sciences, Toxicology, Petroleum Pollution, Imprinting (psychology), Polycyclic Aromatic Hydrocarbons, Zebrafish, chemistry.chemical_classification, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, 0303 health sciences, Larva, biology, photomotor response, anxiety-like behavior, General Medicine, Contamination, Heavy oil, Pollution, [SDV.EE] Life Sciences [q-bio]/Ecology, environment, Light crude oil, Locomotor activity, light crude oil, Offspring, Zoology, Motor Activity, Photomotor response, 03 medical and health sciences, Genomic Imprinting, Aromatase, polycyclic aromatic hydrocarbon, Environmental Chemistry, Ecotoxicology, Animals, 14. Life underwater, Swimming, 030304 developmental biology, 0105 earth and related environmental sciences, Danio rerio, offspring, Transgenerational effect, Anxiety-like behavior, Zebrafish Proteins, biology.organism_classification, Diet, chemistry, 13. Climate action, transgenerational effect, heavy oil, locomotor activity, Water Pollutants, Chemical, Hormone
Abstract: International audience; The release of polycyclic aromatic hydrocarbons (PAHs) into the environment has increased very substantially over the last decades. PAHs are hydrophobic molecules which can accumulate in high concentrations in sediments acting then as major secondary sources. Fish contamination can occur through contact or residence nearby sediments or though dietary exposure. In this study, we analyzed certain physiological traits in unexposed fish (F1) issued from parents (F0) exposed through diet to three PAH mixtures at similar and environmentally relevant concentrations but differing in their compositions. For each mixture, no morphological differences were observed between concentrations. An increase in locomotor activity was observed in larvae issued from fish exposed to the highest concentration of a pyrolytic (PY) mixture. On the contrary, a decrease in locomotor activity was observed in larvae issued from heavy oil mixture (HO). In the case of the third mixture, light oil (LO), a reduction of the diurnal activity was observed during the setup of larval activity. Behavioral disruptions persisted in F1-PY juveniles and in their offspring (F2). Endocrine disruption was analyzed using cyp19a1b:GFP transgenic line and revealed disruptions in PY and LO offspring. Since no PAH metabolites were dosed in larvae, these findings suggest possible underlying mechanisms such as altered parental signaling molecule and/or hormone transferred in the gametes, eventually leading to early imprinting. Taken together, these results indicate that physiological disruptions are observed in offspring of fish exposed to PAH mixtures through diet.
Published: 2015

19. A unified nomenclature of NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER family members in plants

Author: Emilio Fernández, Maurizio Chiurazzi, Jean Christophe Boyer, Mitsunori Seo, Sophie Léran, Laure C. David, Kranthi Varala, Jeanne M. Harris, Ji-Ming Gong, Rebecca Dickstein, Dietmar Geiger, Françoise Daniel-Vedele, Nigel M. Crawford, Benoît Lacombe, Gloria M. Coruzzi, Walter Gassmann, Alain Gojon, Doris Rentsch, Mingyong Zhang, Barbara Ann Halkier, Yi-Fang Tsay, Rainer Hedrich, Anis M. Limami, Brian G. Forde, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Center for Genomics and Systems Biology, Department of Biology [New York], New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Consiglio Nazionale delle Ricerche (CNR), Section of Cell and Developmental Biology, UC San Diego, Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Department of Biological Sciences [Denton], University of North Texas (UNT), Departamento de Bioquýmica y Biologýa Molecular, Edificio Severo Ochoa Baja E, Centre for Sustainable Agriculture, Lancaster Environment Centre, Lancaster University-Lancaster University, Division of Plant Sciences, University of Missouri [Columbia] (Mizzou), University of Missouri System-University of Missouri System-CS Bond Life Sciences Center and Interdisciplinary Plant Group, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), National Key Laboratory of Plant Molecular Genetics and National Center for Plant Gene Research (Shanghai), Chinese Academy of Sciences [Beijing] (CAS)-Shanghai Institutes for Biological Sciences-Institute of Plant Physiology and Ecology, DynaMo Center of Excellence for Dynamic Molecular Interactions (DynaMo), Department of Plant and Environmental Sciences [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Department of Plant Biology, University of Vermont [Burlington], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute of Plant Sciences, University of Bern, RIKEN Center for Sustainable Resource Science [Yokohama] (RIKEN CSRS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Chinese Academy of Sciences [Beijing] (CAS)-South China Botanical Garden, Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), University of Missouri [Columbia], Research Institute of Horticulture and Seeds, Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST-University of Angers, RIKEN Center for Sustainable Resource Science (CSRS), CS Bond Life Sciences Center and Interdisciplinary Plant Group-University of Missouri [Columbia], and University of Missouri System-University of Missouri System
Subjects: 0106 biological sciences, Subfamily, NRT1/PTR, Anion Transport Proteins, Proton-Coupled Oligaopeptide Transporter, Plant Science, Biology, 01 natural sciences, Homology (biology), Substrate Specificity, 03 medical and health sciences, Protein sequencing, Phylogenetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Phylogeny, 030304 developmental biology, Plant Proteins, chemistry.chemical_classification, 0303 health sciences, Phylogenetic tree, Sequence Homology, Amino Acid, Membrane Transport Proteins, food and beverages, Transporter, Nitrate Transporters, Plants, Amino acid, arabidopsis, Biochemistry, chemistry, Nitrate transport, 010606 plant biology & botany
Abstract: International audience; Members of the plant NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family display protein sequence homology with the SLC15/PepT/PTR/POT family of peptide transporters in animals. In comparison to their animal and bacterial counterparts, these plant proteins transport a wide variety of substrates: nitrate, peptides, amino acids, dicarboxylates, glucosinolates, IAA, and ABA. The phylogenetic relationship of the members of the NRT1/PTR family in 31 fully sequenced plant genomes allowed the identification of unambiguous clades, defining eight subfamilies. The phylogenetic tree was used to determine a unified nomenclature of this family named NPF, for NRT1/PTR FAMILY. We propose that the members should be named accordingly: NPFX.Y, where X denotes the subfamily and Y the individual member within the species.
Published: 2014

20. Screening Estrogenic Activities of Chemicals or Mixtures In Vivo Using Transgenic (cyp19a1b-GFP) Zebrafish Embryos

Author: François Brion, Benjamin Piccini, Olivier Cardoso, Yann Le Page, Sok-Keng Tong, Bon Chu Chung, Olivier Kah, Le Corre, Morgane, Institut National de l'Environnement Industriel et des Risques (INERIS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: lcsh:Medicine, 010501 environmental sciences, Toxicology, 01 natural sciences, Green fluorescent protein, Animals, Genetically Modified, MESH: Gene Expression Regulation, Developmental, MESH: Embryonic Development, MESH: Animals, Aromatase, lcsh:Science, Zebrafish, Freshwater Ecology, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Ecology, Estradiol, biology, Stem Cells, Gene Expression Regulation, Developmental, Animal Models, MESH: Estradiol Congeners, Cell biology, MESH: Molecular Mimicry, MESH: Neuroglia, MESH: Estradiol, Stem cell, Neuroglia, Research Article, Neurotoxicology, medicine.medical_specialty, medicine.drug_class, Transgene, Green Fluorescent Proteins, Predictive Toxicology, Embryonic Development, MESH: Zebrafish Proteins, MESH: Animals, Genetically Modified, 03 medical and health sciences, Model Organisms, MESH: Green Fluorescent Proteins, Estradiol Congeners, In vivo, Internal medicine, medicine, Animals, MESH: Aromatase, MESH: Zebrafish, Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, 0105 earth and related environmental sciences, Evolutionary Developmental Biology, Molecular Mimicry, lcsh:R, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Zebrafish Proteins, biology.organism_classification, Endocrinology, Estrogen, Bioindicators, biology.protein, lcsh:Q, Organism Development, Environmental Protection, Developmental Biology
Abstract: International audience; The tg(cyp19a1b-GFP) transgenic zebrafish expresses GFP (green fluorescent protein) under the control of the cyp19a1b gene, encoding brain aromatase. This gene has two major characteristics: (i) it is only expressed in radial glial progenitors in the brain of fish and (ii) it is exquisitely sensitive to estrogens. Based on these properties, we demonstrate that natural or synthetic hormones (alone or in binary mixture), including androgens or progestagens, and industrial chemicals induce a concentration-dependent GFP expression in radial glial progenitors. As GFP expression can be quantified by in vivo imaging, this model presents a very powerful tool to screen and characterize compounds potentially acting as estrogen mimics either directly or after metabolization by the zebrafish embryo. This study also shows that radial glial cells that act as stem cells are direct targets for a large panel of endocrine disruptors, calling for more attention regarding the impact of environmental estrogens and/or certain pharmaceuticals on brain development. Altogether these data identify this in vivo bioassay as an interesting alternative to detect estrogen mimics in hazard and risk assessment perspective.
Published: 2012

21. Neural Progenitors Are Direct Targets of Xenoestrogens in Zebrafish

Author: Bon Chu Chung, François Brion, Mélanie Vosges, Yann Le Page, Olivier Kah, Sok-Keng Tong, Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Jean-Pierre Bourguignon, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, biology, medicine.drug_class, Transgene, Estrogen receptor, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, Radial glial cell, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Endocrine disruptor, Estrogen, medicine, biology.protein, 14. Life underwater, Aromatase, Stem cell, Zebrafish, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Because a large proportion of endocrine disruptor chemicals (EDC) end up in surface waters, aquatic species are particularly vulnerable to their potential effects. In this regard, fish populations must be carefully monitored for fishes are absolutely crucial in terms of biodiversity and protein resources, but also they are extremely valuable as sentinel species. In this chapter, we discuss EDCs effects on the brain of fish, in particular on radial glial cells, which in all vertebrate species are brain stem cells. Indeed, one of the most prominent effect of EDCs in zebrafish is their impact on the cyp19a1b gene that encodes aromatase B. Strikingly, aromatase B is only expressed in radial glial cells that behave as neuronal progenitors. Detailed molecular and whole animal studies in transgenic zebrafish demonstrated the extreme sensitivity of the cyp19a1b gene to estrogen mimics. In particular, doses as low as 1.5 ng/L of EE2 were consistently shown to turn on cyp19a1b gene expression in 2-5 days old zebrafish embryos. As recent studies indicate that estrogens modulate proliferative activity of radial glia progenitors, it is likely that estrogen mimics may have similar activity. The potential outcome of such effects requires thorough investigations, not only in fish but also in developing mammals. In addition, those studies have led to the development of a very sensitive in vivo assay that makes use of cyp19a1b-GFP transgenic embryos whose brain exhibits GFP expression if exposed to any estrogen mimic acting through estrogen receptors.
Published: 2011

22. Neuroendocrine disruption in aquatic species: recent data in zebrafish

Author: Kah, Olivier, Le Page, Yann, Vosges, Mélanie, Tong, Sok-Keng, Porcher, Jean Marc, Chung, Bon-Chu, Brion, François, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Published: 2010

23. Aromatase in the brain of teleost fish: expression, regulation and putative functions

Author: Isabelle Anglade, Sok-Keng Tong, Olivier Kah, Yann Le Page, Farzad Pakdel, Karen Mouriec, Colette Vaillant, Elisabeth Pellegrini, Bon Chu Chung, François Brion, Nicolas Diotel, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Institut National de l'Environnement Industriel et des Risques (INERIS), Original research mentioned in this review was supported by grants from the National Center of Scientific Research, the French Ministry of Research and Education, the European Union (EDEN and PUBERTIMING Project) and the Agence National de la Recherche (Project NEED: CES 2008-011)., and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Embryo, Nonmammalian, Sex Differentiation, Neurogenesis, Molecular Sequence Data, Estrogen receptor, In situ hybridization, Estrogen receptors, Sexual behaviour, Sexual Behavior, Animal, 03 medical and health sciences, Estrogen synthase, 0302 clinical medicine, Aromatase, Internal medicine, medicine, Animals, Cholesterol Side-Chain Cleavage Enzyme, Gonads, cyp19a1b, Phylogeny, 030304 developmental biology, 0303 health sciences, Sexual differentiation, Base Sequence, biology, Endocrine and Autonomic Systems, Estrogen receptor binding, Fishes, Brain, Steroid 17-alpha-Hydroxylase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Preoptic area, Endocrinology, Gene Expression Regulation, Receptors, Estrogen, Sex steroid, biology.protein, Androgens, Seasons, Radial glial cells, Neurosteroids, 030217 neurology & neurosurgery
Abstract: International audience; Unlike that of mammals, the brain of teleost fish exhibits an intense aromatase activity due to the strong expression of one of two aromatase genes (aromatase A or cyp19a1a and aromatase B or cyp19a1b) that arose from a gene duplication event. In situ hybridization, immunohistochemistry and expression of GFP (green fluorescent protein) in transgenic tg(cyp19a1b-GFP) fish demonstrate that aromatase B is only expressed in radial glial cells (RGC) of adult fish. These cells persist throughout life and act as progenitors in the brain of both developing and adult fish. Although aromatase B-positive radial glial cells are most abundant in the preoptic area and the hypothalamus, they are observed throughout the entire central nervous system and spinal cord. In agreement with the fact that brain aromatase activity is correlated to sex steroid levels, the high expression of cyp19a1b is due to an auto-regulatory loop through which estrogens and aromatizable androgens up-regulate aromatase expression. This mechanism involves estrogen receptor binding on an estrogen response element located on the cyp19a1b promoter. Cell specificity is achieved by a mandatory cooperation between estrogen receptors and unidentified glial factors. Given the emerging roles of estrogens in neurogenesis, the unique feature of the adult fish brain suggests that, in addition to classical functions on brain sexual differentiation and sexual behaviour, aromatase expression in radial glial cells could be part of the mechanisms authorizing the maintenance of a high proliferative activity in the brain of fish.
Published: 2010

24. Screening estrogens with the cyp19a1b-GFP transgenic line

Author: Kah, Olivier, Le Page, Yann, Piccini, B., Chung, Bon-Chu, Brion, F., Brébion, Alice, Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology
Published: 2010

25. Brain aromatase: a highly sensitive target of endocrine disruptors in fishes

Author: Kah, Olivier, Le Page, Yann, Tong, Sok-Keng, Pakel, F., Chung, Bon-Chu, Brion, Francois, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Institut National de l'Environnement Industriel et des Risques (INERIS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Published: 2010

26. In vivo imaging and electrical characterization of dividing radial glial cells in the brain of zebrafish

Author: Benquet, Pascal, Pellegrini, Elisabeth, Diotel, Nicolas, Vaillant, Colette, Chung, B. C., Tong, S. K., Senger, Fabrice, Kah, Olivier, Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMethodologies_GENERAL, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Poster
Published: 2009

27. De novo stroids synthesis in the brain of adult zebrafish

Author: Diotel, Nicolas, Anglade, Isabelle, Tong, S. K., Chung, B. C., Kah, Olivier, Vaudry, H., Rego, J.L., Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), De Villemeur, Hervé, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Prix du meilleur poster
Published: 2009

28. Early regulation of brain aromatase (cyp19a1b) by estrogen receptors during zebrafish development

Author: Y Le Page, Isabelle Anglade, Elisabeth Pellegrini, Farzad Pakdel, Sok-Keng Tong, Colette Vaillant, Jean-Jacques Lareyre, Karen Mouriec, Olivier Kah, Bon Chu Chung, Interactions cellulaires et moléculaires (ICM), Centre National de la Recherche Scientifique (CNRS)-IFR140-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Station commune de Recherches en Ichtyophysiologie, Biodiversité et Environnement (SCRIBE), Institut National de la Recherche Agronomique (INRA)-IFR140, Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, animal structures, Embryo, Nonmammalian, Recombinant Fusion Proteins, Estrogen receptor, Biology, Green fluorescent protein, Animals, Genetically Modified, 03 medical and health sciences, 0302 clinical medicine, Aromatase, Internal medicine, medicine, Animals, Protein Isoforms, Receptor, Zebrafish, development, Fulvestrant, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, teleost, Estradiol, fungi, Estrogen Antagonists, Brain, Gene Expression Regulation, Developmental, Embryo, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Zebrafish Proteins, biology.organism_classification, Cell biology, neurogenesis, Endocrinology, Receptors, Estrogen, embryonic structures, biology.protein, neurosteroids, Estrogen receptor alpha, 030217 neurology & neurosurgery, Developmental Biology, estrogen receptor, radial glial cell
Abstract: International audience; Early expression of estrogen receptors (esr) and their role in regulating early expression of cyp19a1b encoding brain aromatase were examined in the brain of zebrafish. Using in toto hybridization and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), a significant increase in the expression of esr1, esr2a, and esr2b was observed between 24 and 48 hours postfertilization (hpf). In toto hybridization demonstrated that esr2a and esr2b, but not esr1, are found in the hypothalamus. Using real-time RT-PCR, an increase in cyp19a1b mRNAs occurs between 24 and 48 hpf, indicating that expression of cyp19a1b is temporally correlated with that of esr. This increase is blocked by the pure anti-estrogen ICI182,780. Furthermore, E2 treatment of cyp19a1b-GFP (green fluorescent protein) transgenic embryos results in appearance of GFP expression in the brain as early as 25 hpf. These results indicate that basal expression of cyp19a1b expression in the brain of developing zebrafish most likely relies upon expression of esr that are fully functional before 25 hpf.
Published: 2009

29. Brain aromatase in teleost fish : expression, regulation and potential functions

Author: Kah, Olivier, Mouriec, Karen, Tong, S. K., Diotel, Nicolas, Le Page, Yann, Anglade, Isabelle, Pakdel, Farzad, Vaillant, Colette, Thieulant, Marie-Lise, Pellegrini, Elisabeth, Chung, B. C., Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2009

30. [Oestrogens and neurogenesis: new functions for an old hormone. Lessons from the zebrafish]

Author: Kah, Olivier, Pellegrini, Elisabeth, Mouriec, Karen, Diotel, Nicolas, Anglade, Isabelle, Vaillant, Colette, Thieulant, Marie-Lise, Tong, Sok-Keng, Brion, François, Chung, Bon-Chu, Pakdel, Farzad, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, Institut National de l'Environnement Industriel et des Risques (INERIS), ANR-CES-2008-011,ANR-CES-2008-011, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and ANR-08-CESA-0011,NEED,Effet neuroendocrines de perturbateurs endocriniens, xénoestrogènes et dioxines, sur les circuits centraux de contrôle de la reproduction, notamment les systèmes GnRH(2008)
Subjects: Mammals, Neurons, Neurogenesis, Stem Cells, Brain, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Estrogens, Nerve Tissue Proteins, Zebrafish Proteins, Birds, astrocyte, Aromatase, Species Specificity, estradiol, Animals, Regeneration, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BDD]Life Sciences [q-bio]/Development Biology, Neuroglia, Cell Division, Zebrafish, radial glial cell
Abstract: International audience; In contrast to other vertebrates, in which the adult brain shows limited adult neurogenesis, teleost fish exhibit an unparalleled capacity to generate new neurons as adults, suggesting that their brains present a highly permissive environment for the maintenance and proliferation of adult progenitors. Here, we examine the hypothesis that one of the factors permitting establishment of this favourable environment is estradiol. Indeed, recent data showed that radial glial cells strongly expressed one of two aromatase duplicated genes. Aromatase is the estrogen-synthesizing enzyme and this observation is of great interest, given that radial glial cells are progenitor cells capable of generating new neurons. Given the well documented roles of estrogens on cell fate, and notably on cell proliferation, these data suggest that estradiol could be involved in maintaining and/or activating these progenitors. Examination of recent data in birds and mammals suggests that the situation in fish could well be an exaggeration of a more general mechanism implicating estrogens in neurogenesis. Indeed, there is accumulating evidence that estrogens are involved in embryonic, adult or reparative neurogenesis in other vertebrates, notably in mammals. Contrairement à celui des Vertébrés qui possède une capacité de neurogenèse limitée au cours de la vie adulte, le cerveau des Poissons Téléostéens est connu pour sa capacité à proliférer tout au long de la vie et ce dans l'ensemble des territoires cérébraux. Nous examinons ici l'hypothèse selon laquelle l'un des facteurs qui pourraient participer au maintien et à la prolifération de progéniteurs neuronaux serait être l'oestradiol. En effet, des résultats récents ont établi que les cellules gliales radiaires, qui persistent dans le cerveau de poisson adulte, expriment fortement le gène cyp19a1b, dont le produit est la cytochrome P450 aromatase, enzyme de synthèse des oestrogènes. Compte tenu des rôles bien connus de l'oestradiol sur la prolifération cellulaire, cette observation est particulièrement intéressante car les cellules gliales radiaires sont des cellules progénitrices capables de générer des neurones. Des données récentes obtenues chez les mammifères et les oiseaux suggèrent que dans de nombreuses situations de neurogenèse embryonnaire, adulte ou réparatrice, il existe un lien entre production d'oestrogènes dans les cellules gliales radiaires ou les astrocytes et l'activité proliférative des ces cellules. Il est donc possible que la situation existant chez les poissons adultes corresponde à l'exploitation d'un mécanisme général impliquant les oestrogènes dans la neurogénèse, à des fins de croissance continue du cerveau.
Published: 2009

31. Le gène cyp19a1b de poisson zèbre : régulation et application à l'étude de la perturbation endocrinienne

Author: Le Page, Yann, Tong, S. K., Mouriec, Karen, Chung, B. C., Kah, Olivier, De Villemeur, Hervé, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Conférence invitée donnée par Y. Le Page; National audience
Published: 2009

32. A cyp19a1b-gfp (aromatase B) transgenic zebrafish line that expresses GFP in radial glial cells

Author: François Brion, Ming Wei Kuo, Marie Madeleine Gueguen, Bon Chu Chung, Elisabeth Pellegrini, Olivier Kah, Sok-Keng Tong, Karen Mouriec, Institute of Molecular Biology (IMB Sinica), Academia Sinica, Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut National de l'Environnement Industriel et des Risques (INERIS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, radial glia, Estrogen receptor, Endogeny, Green fluorescent protein, Animals, Genetically Modified, 0302 clinical medicine, Endocrinology, Estrogen Receptor Modulators, Aromatase, Zebrafish, Fulvestrant, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Microscopy, Confocal, Estradiol, Brain, Gene Expression Regulation, Developmental, aromatase • estrogen synthase • estradiol • estrogen receptors, Immunohistochemistry, Larva, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neuroglia, medicine.drug_class, Transgene, Recombinant Fusion Proteins, Green Fluorescent Proteins, Biology, GFP, 03 medical and health sciences, Genetics, medicine, Animals, development, 030304 developmental biology, Progenitor, transgenic, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Zebrafish Proteins, biology.organism_classification, central nervous system, Molecular biology, brain lipid binding protein, Estrogen, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; Aromatase is an enzyme that catalyzes the synthesis of estrogen in gonads and brain. Teleost fish express aromatase (AroB) strongly in the brain facilitating its detailed examination. To understand the function of AroB in the brain, we generated transgenic zebrafish that expresses green fluorescent protein (GFP) driven by the brain aromatase cyp19a1b promoter. GFP was found in the radial glial cells of transgenic larvae and adult fish that overlap with AroB immunoreactivity in the correct temporal and spatial pattern. GFP was also coexpressed with radial cell marker BLBP, but was not in neurons. In addition, GFP expression in the radial glial cells was stimulated by estrogen, same as endogenous AroB expression. Thus, this transgenic line faithfully mimics the regulation of AroB expression in radial glial cells. It provides a powerful tool to further characterize progenitor radial cells in adult and developing fish and to evaluate estrogenic activities of xenoestrogens and phytoestrogens. genesis 47:67-73, 2009. (c) 2008 Wiley-Liss, Inc.
Published: 2008

33. Heterogeneity of radial glial cells in the brain of zebrafish

Author: Diotel, Nicolas, Mouriec, Karen, Pellegrini, Elisabeth, Tong, S. K., Chung, B. C., Kah, Olivier, Vaillant, Colette, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, De Villemeur, Hervé, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, ComputingMethodologies_GENERAL, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Poster
Published: 2008

34. Mutation of the Arabidopsis NRT1.5 nitrate transporter causes defective root-to-shoot nitrate transport

Author: Marc Lepetit, Yi-Fang Tsay, Geneviève Canivenc, Ya-Yun Wang, Po-Kai Hsu, Alain Gojon, Choun-Sea Lin, Hui-Fen Kuo, Pascal Tillard, Chyn-Bey Tsai, Shan-Hua Lin, Huey-Ling Lin, Institute of Molecular Biology (IMB Sinica), Academia Sinica, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Department of Horticulture, National Chung Hsing University, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: 0106 biological sciences, nitrate transporter, Mutant, Arabidopsis, Plant Science, 01 natural sciences, Plant Roots, chemistry.chemical_compound, Nitrate, Génétique des plantes, Arabidopsis thaliana, Peptide Transporter PTR, Cloning, Molecular, Chromatography, High Pressure Liquid, In Situ Hybridization, Research Articles, 0303 health sciences, food and beverages, Nitrate Transporters, Biochemistry, Nitrate transport, Plant Shoots, Anion Transport Proteins, Molecular Sequence Data, Biology, Plants genetics, 03 medical and health sciences, physiologie végétale, nitrate, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, mutant, transport membranaire, Amino Acid Sequence, Ion transporter, 030304 developmental biology, Ion Transport, Nitrates, Sequence Homology, Amino Acid, Arabidopsis Proteins, PEPTIDE, TRANSPORTER PTR, NRT1.1, NRT1.2, NITRATE TRANSPORTER, ROOT, BIOLOGIE DU DEVELOPPEMENT, Cell Membrane, fungi, Xylem, Cell Biology, biology.organism_classification, racine, Pericycle, chemistry, Mutation, 010606 plant biology & botany
Abstract: Little is known about the molecular and regulatory mechanisms of long-distance nitrate transport in higher plants. NRT1.5 is one of the 53 Arabidopsis thaliana nitrate transporter NRT1 (Peptide Transporter PTR) genes, of which two members, NRT1.1 (CHL1 for Chlorate resistant 1) and NRT1.2, have been shown to be involved in nitrate uptake. Functional analysis of cRNA-injected Xenopus laevis oocytes showed that NRT1.5 is a low-affinity, pH-dependent bidirectional nitrate transporter. Subcellular localization in plant protoplasts and in planta promoter-β-glucuronidase analysis, as well as in situ hybridization, showed that NRT1.5 is located in the plasma membrane and is expressed in root pericycle cells close to the xylem. Knockdown or knockout mutations of NRT1.5 reduced the amount of nitrate transported from the root to the shoot, suggesting that NRT1.5 participates in root xylem loading of nitrate. However, root-to-shoot nitrate transport was not completely eliminated in the NRT1.5 knockout mutant, and reduction of NRT1.5 in the nrt1.1 background did not affect root-to-shoot nitrate transport. These data suggest that, in addition to that involving NRT1.5, another mechanism is responsible for xylem loading of nitrate. Further analyses of the nrt1.5 mutants revealed a regulatory loop between nitrate and potassium at the xylem transport step.
Published: 2008

35. Characterization of a transgenic zebrafish line expressing GFP in aromatase B-positive and BLBP positive radial glia progenitor cells

Author: Mouriec, Karen, Pellegrini, Elisabeth, Kah, Olivier, Chung, B. C., Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Biology (IMB Sinica), Academia Sinica, De Villemeur, Hervé, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, ComputingMethodologies_GENERAL, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Poster
Published: 2007

36. Generation of Cyp19b : GFP transgenic line in zebrafish, Danio rerio

Author: Tong, S. K., Mouriec, Karen, Kah, Olivier, Chung, B. C., De Villemeur, Hervé, Institute of Molecular Biology (IMB Sinica), Academia Sinica, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, ComputingMethodologies_GENERAL, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: Poster
Published: 2007

37. Characterization of duplicated Zebrafish cyp19 genes

Author: Sok-Keng Tong, Yi-Lin Yan, Pei Hung Hsiao, Yann Guiguen, John H. Postlethwait, Evelyn Feng Lin Chiang, Bon Chu Chung, Institute of Molecular Biology (IMB Sinica), Academia Sinica, Institute of Neuroscience, University of Oregon [Eugene], National Taiwan University Hospital, Station commune de Recherches en Ichtyophysiologie, Biodiversité et Environnement (SCRIBE), and Institut National de la Recherche Agronomique (INRA)
Subjects: DNA, Complementary, Sex Differentiation, gene cyp19, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Evolution, Molecular, 03 medical and health sciences, Aromatase, 0302 clinical medicine, Gene Duplication, Genetic model, Gene duplication, Animals, [INFO]Computer Science [cs], Amino Acid Sequence, Peptide sequence, Zebrafish, Gene, 030304 developmental biology, Regulation of gene expression, Genetics, 0303 health sciences, Ovary, Brain, Cytochrome P450, General Medicine, Sex Determination Processes, biology.organism_classification, zebrafish, Gene Expression Regulation, biology.protein, Female, Animal Science and Zoology, 030217 neurology & neurosurgery
Abstract: International audience; The zebrafish has recently been developed as a good genetic model system. We report here the use of zebrafish to study the regulation of estrogen biosynthesis. The CYP19 gene encodes cytochrome P450 aromatase, which catalyzes the synthesis of estrogens. Two cyp19 genes, termed cyp19a and cyp19b, have been isolated from zebrafish. Sequence comparison shows that Cyp19a and Cyp19b belong to two separate Cyp19 subfamilies. The cyp19a gene is expressed in the ovary, whereas cyp19b is expressed in the brain. The cyp19a and cyp19b genes are located on zebrafish chromosomes LG 18 and 25, respectively. Our data indicate that these gene loci arose through an ancient chromosomal duplication event. The expression of duplicated genes in distinct tissues may have evolutionary significance.
Published: 2001

38. Author Correction: Subclassification of obesity for precision prediction of cardiometabolic diseases.

Author: Coral DE, Smit F, Farzaneh A, Gieswinkel A, Tajes JF, Sparsø T, Delfin C, Bauvin P, Wang K, Temprosa M, De Cock D, Blanch J, Fernández-Real JM, Ramos R, Ikram MK, Gomez MF, Kavousi M, Panova-Noeva M, Wild PS, van der Kallen C, Adriaens M, van Greevenbroek M, Arts I, Le Roux C, Ahmadizar F, Frayling TM, Giordano GN, Pearson ER, and Franks PW
Published: 2024
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39. m6A sites in the coding region trigger translation-dependent mRNA decay.

Author: Zhou Y, Ćorović M, Hoch-Kraft P, Meiser N, Mesitov M, Körtel N, Back H, Naarmann-de Vries IS, Katti K, Obrdlík A, Busch A, Dieterich C, Vaňáčová Š, Hengesbach M, Zarnack K, and König J
Abstract: N 6 -Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. Here, using human cells, we reveal that m6A sites in the coding sequence (CDS) trigger CDS-m6A decay (CMD), a pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors. Mechanistically, CMD depends on translation, whereby m6A deposition in the CDS triggers ribosome pausing and transcript destabilization. The subsequent decay involves the translocation of the CMD target transcripts to processing bodies (P-bodies) and recruitment of the m6A reader protein YT521-B homology domain family protein 2 (YTHDF2). Our findings highlight CMD as a previously unknown pathway, which is particularly important for controlling the expression of developmental regulators and retrogenes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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40. Intrinsically disordered RNA-binding motifs cooperate to catalyze RNA folding and drive phase separation.

Author: Niedner-Boblenz A, Monecke T, Hennig J, Klostermann M, Hofweber M, Davydova E, Gerber AP, Anosova I, Mayer W, Müller M, Heym RG, Janowski R, Paillart JC, Dormann D, Zarnack K, Sattler M, and Niessing D
Abstract: RNA-binding proteins are essential for gene regulation and the spatial organization of cells. Here, we report that the yeast ribosome biogenesis factor Loc1p is an intrinsically disordered RNA-binding protein with eight repeating positively charged, unstructured nucleic acid binding (PUN) motifs. While a single of these previously undefined motifs stabilizes folded RNAs, multiple copies strongly cooperate to catalyze RNA folding. In the presence of RNA, these multivalent PUN motifs drive phase separation. Proteome-wide searches in pro- and eukaryotes for proteins with similar arrays of PUN motifs reveal a strong enrichment in RNA-mediated processes and DNA remodeling. Thus, PUN motifs are potentially involved in a large variety of RNA- and DNA-related processes by concentrating them in membraneless organelles. The general function and wide distribution of PUN motifs across species suggest that in an ancient 'RNA world' PUN-like motifs may have supported the correct folding of early ribozymes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2024
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41. Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy.

Author: Prieto-Garcia C, Matkovic V, Mosler T, Li C, Liang J, Oo JA, Haidle F, Mačinković I, Cabrera-Orefice A, Berkane R, Giuliani G, Xu F, Jacomin AC, Tomaskovic I, Basoglu M, Hoffmann ME, Rathore R, Cetin R, Boutguetait D, Bozkurt S, Hernández Cañás MC, Keller M, Busam J, Shah VJ, Wittig I, Kaulich M, Beli P, Galej WP, Ebersberger I, Wang L, Münch C, Stolz A, Brandes RP, Tse WKF, Eimer S, Stainier DYR, Legewie S, Zarnack K, Müller-McNicoll M, and Dikic I
Subjects: Animals, Humans, Mice, HEK293 Cells, HeLa Cells, Proteasome Endopeptidase Complex metabolism, Protein Folding, RNA Splice Sites, RNA, Messenger metabolism, RNA, Messenger genetics, Spliceosomes metabolism, Ubiquitin metabolism, Zebrafish genetics, Autophagy, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, RNA Splicing, Ubiquitin-Specific Proteases metabolism, Ubiquitin-Specific Proteases genetics, Ubiquitination
Abstract: RNA splicing enables the functional adaptation of cells to changing contexts. Impaired splicing has been associated with diseases, including retinitis pigmentosa, but the underlying molecular mechanisms and cellular responses remain poorly understood. In this work, we report that deficiency of ubiquitin-specific protease 39 (USP39) in human cell lines, zebrafish larvae, and mice led to impaired spliceosome assembly and a cytotoxic splicing profile characterized by the use of cryptic 5' splice sites. Disruptive cryptic variants evaded messenger RNA (mRNA) surveillance pathways and were translated into misfolded proteins, which caused proteotoxic aggregates, endoplasmic reticulum (ER) stress, and, ultimately, cell death. The detrimental consequence of splicing-induced proteotoxicity could be mitigated by up-regulating the ubiquitin-proteasome system and selective autophagy. Our findings provide insight into the molecular pathogenesis of spliceosome-associated diseases.
Published: 2024
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42. Potential vs Challenges of Expanding the Protein Universe With Genetic Code Expansion in Eukaryotic Cells.

Author: Bhattacharjee R and Lemke EA
Subjects: Protein Biosynthesis, Codon genetics, Humans, Proteins genetics, Proteins metabolism, Animals, Protein Processing, Post-Translational, Genetic Code, Eukaryotic Cells metabolism
Abstract: Following decades of innovation and perfecting, genetic code expansion has become a powerful tool for in vivo protein modification. Some of the major hurdles that had to be overcome include suboptimal performance of GCE-specific translational components in host systems, competing cellular processes, unspecific modification of the host proteome and limited availability of codons for reassignment. Although strategies have been developed to overcome these challenges, there is critical need for further advances. Here we discuss the current state-of-the-art in genetic code expansion technology and the issues that still need to be addressed to unleash the full potential of this method in eukaryotic cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘R.B. declares no competing financial interest. E.A.L. holds several patents related to genetic code expansion and is a cofounder and consultant of Veraxa GmbH, a company specialized on generation of antibody drug conjugates via GCE.’., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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43. Tuning the Functionality of Designer Translating Organelles with Orthogonal tRNA Synthetase/tRNA Pairs.

Author: Sushkin ME, Jung M, and Lemke EA
Subjects: Amino Acids metabolism, Methanosarcina genetics, Methanosarcina enzymology, Methanosarcina metabolism, Amino Acyl-tRNA Synthetases metabolism, Amino Acyl-tRNA Synthetases genetics, RNA, Transfer metabolism, RNA, Transfer genetics, Genetic Code, Protein Biosynthesis, Organelles metabolism
Abstract: Site-specific incorporation of noncanonical amino acids (ncAAs) can be realized by genetic code expansion (GCE) technology. Different orthogonal tRNA synthetase/tRNA (RS/tRNA) pairs have been developed to introduce a ncAA at the desired site, delivering a wide variety of functionalities that can be installed into selected proteins. Cytoplasmic expression of RS/tRNA pairs can cause a problem with background ncAA incorporation into host proteins. The application of orthogonally translating organelles (OTOs), inspired by the concept of phase separation, provides a solution for this issue in mammalian cells, allowing site-specific and protein-selective ncAA incorporation. So far, only Methanosarcina mazei (Mm) pyrrolysyl-tRNA synthetase (PylRS) has been used within OTOs, limiting the method's potential. Here, we explored the implementation of four other widely used orthogonal RS/tRNA pairs with OTOs, which, to our surprise, were unsuccessful in generating mRNA-selective GCE. Next, we tested several experimental solutions and developed a new chimeric phenylalanyl-RS/tRNA pair that enables ncAA incorporation in OTOs in a site-specific and protein-selective manner. Our work reveals unaccounted design constraints in the spatial engineering of enzyme functions using designer organelles and presents a strategy to overcome those in vivo. We then discuss current limitations and future directions of in-cell engineering in general and protein engineering using GCE specifically., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “E.A.L. holds patents related to OTOs. M.E.S. and M.J. declare no competing interests.”., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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44. Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome.

Author: Arroyo M, Casas-Delucchi CS, Pabba MK, Prorok P, Pradhan SK, Rausch C, Lehmkuhl A, Maiser A, Buschbeck M, Pasque V, Bernstein E, Luck K, and Cardoso MC
Subjects: Animals, Chromosomes, Human, X genetics, DNA Helicases metabolism, DNA Helicases genetics, Minichromosome Maintenance Complex Component 3 genetics, Minichromosome Maintenance Complex Component 3 metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, X Chromosome Inactivation genetics, Mice, DNA Replication genetics, Histones metabolism, Histones genetics, Nucleosomes metabolism, Nucleosomes genetics, Replication Origin genetics
Abstract: MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability. Moreover, macroH2A1, but not macroH2A2, regulates the number of nano replication foci in the Xi, and macroH2A1 downregulation increases DNA loop sizes corresponding to replicons. This relates to macroH2A1 regulating replicative helicase loading during G1 by interacting with it. We mapped this interaction to a phenylalanine in macroH2A1 that is not conserved in macroH2A2 and the C-terminus of Mcm3 helicase subunit. We propose that macroH2A1 enhances the licensing of pre-replication complexes via DNA helicase interaction and loading onto the Xi., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2024
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45. ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner.

Author: Wunderlich TM, Deshpande C, Paasche LW, Friedrich T, Diegmüller F, Haddad E, Kreienbaum C, Naseer H, Stebel SE, Daus N, Leers J, Lan J, Trinh VT, Vázquez O, Butter F, Bartkuhn M, Mackay JP, and Hake SB
Abstract: The evolutionarily conserved histone variant H2A.Z plays a crucial role in various DNA-based processes, but the mechanisms underlying its activity are not completely understood. Recently, we identified the zinc finger (ZF) protein ZNF512B as a protein associated with H2A.Z, HMG20A and PWWP2A. Here, we report that high levels of ZNF512B expression lead to nuclear protein and chromatin aggregation foci that form in a manner that is dependent on the ZF domains of ZNF512B. Notably, we demonstrate ZNF512B binding to the nucleosome remodeling and deacetylase (NuRD) complex. We discover a conserved amino acid sequence within ZNF512B that resembles the NuRD-interaction motif (NIM) previously identified in FOG-1 and other transcriptional regulators. By solving the crystal structure of this motif bound to the NuRD component RBBP4 and by applying several biochemical and biophysical assays, we demonstrate that this internal NIM is both necessary and sufficient for robust and high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as a repressor of gene expression that can act in both NuRD-dependent and -independent ways. Our study might have implications for diseases in which ZNF512B expression is deregulated, such as cancer and neurodegenerative diseases, and hints at the existence of more proteins as potential NuRD interactors., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2024
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46. Different risk and protective factors predict change of planning ability in middle versus older age.

Author: Unterrainer JM, Petersen J, Schmidt P, Ernst M, Wirtz MA, Reinwarth AC, Wicke F, Ghaemi Kerahrodi J, Michal M, Münzel T, König J, Lackner KJ, Pfeiffer N, Tüscher O, Galle PR, Beutel M, and Wild PS
Subjects: Humans, Middle Aged, Male, Female, Aged, Adult, Risk Factors, Aged, 80 and over, Protective Factors, Prospective Studies, Polymorphism, Single Nucleotide, Cognition physiology, Apolipoproteins E genetics, Age Factors, Cognitive Dysfunction
Abstract: Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age., (© 2024. The Author(s).)
Published: 2024
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47. Selective RNA pseudouridinylation in situ by circular gRNAs in designer organelles.

Author: Schartel L, Jann C, Wierczeiko A, Butto T, Mündnich S, Marchand V, Motorin Y, Helm M, Gerber S, and Lemke EA
Subjects: Humans, HEK293 Cells, RNA, Circular metabolism, RNA, Circular genetics, RNA metabolism, RNA genetics, HeLa Cells, Pseudouridine metabolism, Organelles metabolism, RNA Editing, RNA, Guide, CRISPR-Cas Systems metabolism, RNA, Guide, CRISPR-Cas Systems genetics, RNA, Messenger metabolism, RNA, Messenger genetics
Abstract: RNA modifications play a pivotal role in the regulation of RNA chemistry within cells. Several technologies have been developed with the goal of using RNA modifications to regulate cellular biochemistry selectively, but achieving selective and precise modifications remains a challenge. Here, we show that by using designer organelles, we can modify mRNA with pseudouridine in a highly selective and guide-RNA-dependent manner. We use designer organelles inspired by concepts of phase separation, a central tenet in developing artificial membraneless organelles in living mammalian cells. In addition, we use circular guide RNAs to markedly enhance the effectiveness of targeted pseudouridinylation. Our studies introduce spatial engineering through optimized RNA editing organelles (OREO) as a complementary tool for targeted RNA modification, providing new avenues to enhance RNA modification specificity., (© 2024. The Author(s).)
Published: 2024
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48. Subclassification of obesity for precision prediction of cardiometabolic diseases.

Author: Coral DE, Smit F, Farzaneh A, Gieswinkel A, Tajes JF, Sparsø T, Delfin C, Bauvin P, Wang K, Temprosa M, De Cock D, Blanch J, Fernández-Real JM, Ramos R, Ikram MK, Gomez MF, Kavousi M, Panova-Noeva M, Wild PS, van der Kallen C, Adriaens M, van Greevenbroek M, Arts I, Le Roux C, Ahmadizar F, Frayling TM, Giordano GN, Pearson ER, and Franks PW
Abstract: Obesity and cardiometabolic disease often, but not always, coincide. Distinguishing subpopulations within which cardiometabolic risk diverges from the risk expected for a given body mass index (BMI) may facilitate precision prevention of cardiometabolic diseases. Accordingly, we performed unsupervised clustering in four European population-based cohorts (N ≈ 173,000). We detected five discordant profiles consisting of individuals with cardiometabolic biomarkers higher or lower than expected given their BMI, which generally increases disease risk, in total representing ~20% of the total population. Persons with discordant profiles differed from concordant individuals in prevalence and future risk of major adverse cardiovascular events (MACE) and type 2 diabetes. Subtle BMI-discordances in biomarkers affected disease risk. For instance, a 10% higher probability of having a discordant lipid profile was associated with a 5% higher risk of MACE (hazard ratio in women 1.05, 95% confidence interval 1.03, 1.06, P = 4.19 × 10 -10 ; hazard ratio in men 1.05, 95% confidence interval 1.04, 1.06, P = 9.33 × 10 -14 ). Multivariate prediction models for MACE and type 2 diabetes performed better when incorporating discordant profile information (likelihood ratio test P < 0.001). This enhancement represents an additional net benefit of 4-15 additional correct interventions and 37-135 additional unnecessary interventions correctly avoided for every 10,000 individuals tested., Competing Interests: Competing interests: T.S. and C.D. are employees and shareholders of Novo Nordisk. M.F.G. has received financial and nonfinancial (in kind) support from Boehringer Ingelheim Pharma GmbH, JDRF International, Eli Lilly, AbbVie, Sanofi-Aventis, Astellas, Novo Nordisk A/S and Bayer AG, within European Union grant H2020-JTI-lMl2-2015-05 (grant agreement no. 115974 - BEAt-DKD). She has also received financial and in kind support from Novo Nordisk, Pfizer, Follicum, Coegin Pharma, Abcentra, Probi and Johnson & Johnson, within a project funded by the Swedish Foundation for Strategic Research on precision medicine in diabetes (LUDC-IRC, grant no. 15-0067). M.F.G. has received personal consultancy fees from Lilly and Tribune Therapeutics AB. M.P.-N. is an employee of Boehringer Ingelheim. Outside the submitted work, P.S.W. has received consulting fees from Astra Zeneca, research funding from Bayer AG, research funding, consulting and lecturing fees from Bayer Health Care, lecturing fees from Bristol Myers Squibb, research funding and consulting fees from Boehringer Ingelheim, research funding and consulting fees from Daiichi Sankyo Europe, consulting fees and nonfinancial support from Diasorin, nonfinancial research support from I.E.M., research funding and consulting fees from Novartis Pharma, lecturing fees from Pfizer Pharma, nonfinancial grants from Philips Medical Systems, and research funding and consulting fees from Sanofi-Aventis. C.L.R. reports grants from the Irish Research Council, Science Foundation Ireland, Anabio and the Health Research Board. He serves on advisory boards and speakers panels of Novo Nordisk, Roche, Herbalife, GI Dynamics, Eli Lilly, Johnson & Johnson, Glia, Irish Life Health, Boehringer Ingelheim, Currax, Zealand Pharma, Keyron, Astra Zeneca and Rhythm Pharma. C.L.R. is a member of the Irish Society for Nutrition and Metabolism outside the area of work commented on here. C.L.R. provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a shareholder in these clinics. He was the chief medical officer and director of the Medical Device Division of Keyron in 2021. Both of these are unremunerated positions. C.L.R. was a previous investor in Keyron, which develops endoscopically implantable medical devices intended to mimic the surgical procedures of sleeve gastrectomy and gastric bypass. No patients have been included in any of Keyron’s studies and they are not listed on the stock market. C.L.R. was gifted stock holdings in September 2021 and divested all stock holdings in Keyron in September 2021. He continues to provide scientific advice to Keyron for no remuneration. Outside the submitted work, E.R.P. has received honoraria from Novo Nordisk, Lilly and Illumina. Within the past five years, P.W.F. has received consulting honoraria from Eli Lilly Inc., Novo Nordisk Foundation, Novo Nordisk A/S, UBS and Zoe Ltd, has been an employee of the Novo Nordisk Foundation, and has been on advisory boards for the Danish Diabetes and Endocrine Academy, Novo Nordisk A/S, Hamad Medical Corporation and Zoe Ltd. P.W.F. has also received investigator-initiated grants (paid to institution) from numerous pharmaceutical companies as part of the Innovative Medicines Initiative of the European Union. The other authors declare no competing interests., (© 2024. The Author(s).)
Published: 2024
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49. 5-Formylcytosine is an activating epigenetic mark for RNA Pol III during zygotic reprogramming.

Author: Parasyraki E, Mallick M, Hatch V, Vastolo V, Musheev MU, Karaulanov E, Gopanenko A, Moxon S, Méndez-Lago M, Han D, Schomacher L, Mukherjee D, and Niehrs C
Subjects: Animals, Mice, RNA, Transfer metabolism, RNA, Transfer genetics, Xenopus laevis metabolism, Xenopus laevis embryology, Xenopus laevis genetics, Xenopus metabolism, Xenopus embryology, Xenopus genetics, Female, Cellular Reprogramming, Gene Expression Regulation, Developmental, Oocytes metabolism, Cytosine metabolism, Cytosine analogs & derivatives, Zygote metabolism, RNA Polymerase III metabolism, RNA Polymerase III genetics, Epigenesis, Genetic
Abstract: 5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In Xenopus embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed tRNA genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as tRNA expression. Concordantly, 5fC modification of a tRNA transgene enhances its expression in vivo. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
Published: 2024
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50. Assessment of psychological resilience in a large cohort of the general population: Validation and norm values of the RS-5.

Author: Reinwarth AC, Hahad O, Ghaemi Kerahrodi J, Brähler E, Lieb K, Gilan D, Zahn D, Chalabi J, Schuster AK, Schepers M, Lackner KJ, Schattenberg JM, Ruf W, Wild PS, Daiber A, Michal M, Beutel ME, and Münzel T
Subjects: Humans, Female, Male, Middle Aged, Aged, Adult, Aged, 80 and over, Cohort Studies, Surveys and Questionnaires, Anxiety psychology, Anxiety epidemiology, Depression epidemiology, Depression psychology, Reference Values, Resilience, Psychological, Psychometrics methods
Abstract: Background: Psychological resilience is known as a protective factor against mental health disorders for which valid measures are indispensable. The present work aims to evaluate the Resilience Scale-5 (RS-5) psychometrically, and provide norm values., Methods: Data from the Gutenberg Health Study (GHS), encompassing 7,496 participants aged 25 to 86, spanning the years 2017 to 2022, was used. Selectivity, item difficulty, internal consistency, construct and factor validity, as well as factorial invariance were tested. Additionally, correlations and associations with depression, anxiety, and sociodemographic factors were determined. Furthermore, norm values were provided., Results: The RS-5 displayed robust psychometric properties. Participants reported an average resilience score of 28.94 (SD = 5.53, median = 30, IQR = 6, range = 5-35), with those aged ≥75 exhibiting the highest resilience levels (M = 30.21, SD = 5.75, median = 32, IQR = 7). The RS-5 displayed a very good model fit, affirming measurement invariance across sex and age decades. Construct validity found support through anticipated intercorrelations with related psychological constructs. Significant correlations (p < .001) linked higher resilience with female gender, advanced age, higher education, elevated household income, and diminished psychological distress., Conclusion: The RS-5 emerged as a reliable and economic instrument for assessing psychological resilience in individuals aged 25 to 86. The study unraveled distinct sociodemographic characteristics significantly tied to resilience levels within this cohort. In contributing recent norm values tailored to the German population, this research enhances the practical applicability of the RS-5 across diverse contexts and enriches our comprehension of the demographic nuances associated with psychological resilience., Competing Interests: Philipp S. Wild is funded by the Federal Ministry of Education and Research (BMBF 01EO1503). P.S.W. and T.M. are PIs and O.H. is a Young Scientist of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. There are no patents, products in development, or marketed products to declare. This does not alter the authors’ adherence to all of the journal policies on sharing data and materials. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The other authors A.C.R., J. G.-K., E.B., K.L., D.G., D.Z., J.C., A.K.S., M.S., K.J.L., J.M.S., W.R., A.D., M.M, and M.E.B. declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Reinwarth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2024
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