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1. ER-mitochondria cross-talk is regulated by the Ca 2+ sensor NCS1 and is impaired in Wolfram syndrome

Author

Jennifer Rieusset, Benjamin Delprat, Dan Milea, Chantal Cazevieille, Mélanie Quiles, Marc Thiry, Paolo Pinton, Julia Korchagina, Claire Angebault, Alberto Danese, Camille Mégy, Delphine Bonnet-Wersinger, Simone Patergnani, Alain Lacampagne, Corentin Affortit, Christian P. Hamel, Jolanta Jagodzinska, Jérémy Fauconnier, Cécile Delettre, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Ferrara (UniFE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Service d'ophtalmologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Singapore Eye Research Institute [Singapore] (SERI), Centre de référence pour les maladies génétiques sensorielles [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), We are indebted to the INSERM and Université Montpellier for providing institutional support and to the patient associations Union National des Aveugles et Déficients Visuels (UNADEV) and Association Syndrome de Wolfram for their financial support. This work was supported by grants from the Agence Nationale pour la Recherche (ANR-12-JSV1-0008-01), Fondation pour la Recherche Médicale, and Fondation de France. C.A. was supported by the Fondation de France., ANR-12-JSV1-0001,LIPIDOPAIN,Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Ferrara [Ferrara], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-12-JSV1-0001,LIPIDOPAIN,Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux TRP dans l'hypersensibilité viscérale(2012), Institut des Neurosciences de Montpellier (INM), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Delprat, Benjamin, and Jeunes Chercheuses et Jeunes Chercheurs - Implication des métabolites des acide gars polyinsaturés et des récepteurs canaux 'TRP' dans l'hypersensibilité viscérale - - LIPIDOPAIN2012 - ANR-12-JSV1-0001 - JC - VALID

Subjects
0301 basic medicine, endocrine system diseases, Wolfram syndrome, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, Biochemistry, NO, stress, 03 medical and health sciences, chemistry.chemical_compound, neurodegenaration, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Inositol, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, endoplasmic reticulum membranes, Biochemistry, Molecular Biology, Cell Biology, endoplasmic reticulum membranes, mitfusin 2, protein, neurodegenaration, activation, transport, stress, biology, Chemistry, Endoplasmic reticulum, HEK 293 cells, Cell Biology, medicine.disease, mitfusin 2, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Neuronal calcium sensor-1, transport, biology.protein, activation, Signal transduction, protein
Abstract

International audience; Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3R) to promote Ca2+ transfer between the ER and mitochondria. In addition, we found that NCS1 abundance was reduced in WFS1-null patient fibroblasts, which showed reduced ER-mitochondria interactions and Ca2+ exchange. Moreover, in WFS1-deficient cells, NCS1 overexpression not only restored ER-mitochondria interactions and Ca2+ transfer but also rescued mitochondrial dysfunction. Our results describe a key role of NCS1 in ER-mitochondria cross-talk, uncover a pathogenic mechanism for Wolfram syndrome, and potentially reveal insights into the pathogenesis of other neurodegenerative diseases.

Published
2018

2. p27Kip1 Modulates Axonal Transport by Regulating α-Tubulin Acetyltransferase 1 Stability

Author

Morelli , Giovanni, Even , Aviel, Gladwyn-Ng , Ivan, Le Bail , Romain, Shilian , Michal, Godin , Juliette D., Peyre , Elise, Hassan , Bassem, Besson , Arnaud, Rigo , Jean-Michel, Weil , Miguel, Brône , Bert, Nguyen , Laurent, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer de Toulouse - Oncopole ( IUCT Oncopole - UMR 1037 ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Université de Liège, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS)

Subjects
dacapo, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], p27(Kip1), HDAC6, ATAT1, lcsh:Biology (General), nervous system, alpha-tubulin, cerebral cortex, Drosophila, axonal transport, lcsh:QH301-705.5, mouse, acetylation
Abstract

Summary: The protein p27Kip1 plays roles that extend beyond cell-cycle regulation during cerebral cortex development, such as the regulation of neuronal migration and neurite branching via signaling pathways that converge on the actin and microtubule cytoskeletons. Microtubule-dependent transport is essential for the maturation of neurons and the establishment of neuronal connectivity though synapse formation and maintenance. Here, we show that p27Kip1 controls the transport of vesicles and organelles along the axon of mice cortical projection neurons in vitro. Moreover, suppression of the p27Kip1 ortholog, dacapo, in Drosophila melanogaster disrupts axonal transport in vivo, leading to the reduction of locomotor activity in third instar larvae and adult flies. At the molecular level, p27Kip1 stabilizes the α-tubulin acetyltransferase 1, thereby promoting the acetylation of microtubules, a post-translational modification required for proper axonal transport. : Morelli et al. report that p27Kip1/Dacapo modulates the acetylation of microtubules in axons via stabilization of ATAT1, the main α-tubulin acetyltransferase. Its conditional loss leads to the reduction of bidirectional axonal transport of vesicles and mitochondria in vitro in mice and in vivo in Drosophila. Keywords: p27Kip1, dacapo, acetylation, axonal transport, ATAT1, alpha-tubulin, HDAC6, Drosophila, mouse, cerebral cortex

Published
2018

3. Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly

Author

Nicolas Thelen, Christian Alfano, Pierre Vanderhaeghen, Thérèse Couderc, Maryse Bonnière, Michelle America, Giovanni Morelli, Ikuo K. Suzuki, Catherine Creppe, Bettina Bessières, Lluís Cordón-Barris, Laurent Nguyen, Marc Lecuit, Marie Flamand, Marc Thiry, Férechté Encha-Razavi, Ivan Gladwyn-Ng, GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Biologie des Infections - Biology of Infection, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], BIOMED [Hasselt], Hasselt University (UHasselt), Département d’Histologie-Embryologie-Cytogénétique, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles (ULB), Virologie Structurale, Institut Pasteur [Paris], Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The authors are thankful for technical help from the GIGA-Imaging Platform of ULg, M. Leruez-Ville for human sample collection, P.V. Drion, E.D. Valentin and C. Grignet for the flaviviral facility, C. d’Alessandro, M. Sambon and M. Lavina for technical assistance, E. Simon-Loriere for sharing ZIKV quantification protocol, and E. Peyre for graphical assistance. L.N., I.G.-N. and C.C. receive financial support from F.R.S.-F.N.R.S. This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement N° 734548 (to L.N. and M.L.) and by the European Virus Archives goes Global (EVAg) project under grant agreement N° 653316. M.L. is also funded by Institut Pasteur, Inserm and LabEx IBEID. L.N. and P.V. are funded by F.R.S.-F.N.R.S., the Fonds Léon Fredericq, the Fondation Médicale Reine Elisabeth, the Fondation Simone et Pierre Clerdent and the Belgian Science Policy (IAP-VII network P7/20). L.N. is funded by ARC (ARC11/16-01) and the ERANET Neuron STEM-MCD, P.V. is funded by the WELBIO Program of the Walloon Region, the AXA Research Fund, the Fondation ULB, ERANET Neuron Microkin, ERANET E-rare Euromicro and ERC-2013 ERC-2013-AG-340020., European Project: 734548,ZIKAlliance(2016), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hasselt University, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Libre de Bruxelles [Bruxelles] (ULB), Welbio, and Free University of Brussels (BELGIUM)

Subjects
Gene Expression Regulation, Viral, 0301 basic medicine, Microcephaly, Mice, Transgenic, Nerve Tissue Proteins, Biology, Mice, Neuroblastoma, 03 medical and health sciences, Fetus, Cell Line, Tumor, medicine, Animals, Humans, Progenitor cell, Protein Unfolding, Activating Transcription Factor 3, Zika Virus Infection, General Neuroscience, Endoplasmic reticulum, Neurogenesis, Brain, Interferon-alpha, Zika Virus, Embryo, Mammalian, Endoplasmic Reticulum Stress, medicine.disease, Embryonic stem cell, Neural stem cell, 3. Good health, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Unfolded protein response, Neuroscience
Abstract

Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice. The authors are thankful for technical help from the GIGA-Imaging Platform of ULg; M. Leruez-Ville for human sample collection; P.V. Drion, E.D. Valentin and C. Grignet for the flaviviral facility; C. d'Alessandro, M. Sambon and M. Lavina for technical assistance; E. Simon-Loriere for sharing ZIKV quantification protocol; and E. Peyre for graphical assistance. L.N., I.G.-N. and C. C. receive financial support from F.R.S.-F.N.R.S. This work was supported by the European Union's Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement No 734548 (to L.N. and M.L.) and by the European Virus Archives goes Global (EVAg) project under grant agreement No 653316. M.L. is also funded by Institut Pasteur, Inserm and LabEx IBEID. L.N. and P.V. are funded by F.R.S.-F.N.R.S., the Fonds Leon Fredericq, the Fondation Medicale Reine Elisabeth, the Fondation Simone et Pierre Clerdent and the Belgian Science Policy (IAP-VII network P7/20). L.N. is funded by ARC (ARC11/16-01) and the ERANET Neuron STEM-MCD; P.V. is funded by the WELBIO Program of the Walloon Region, the AXA Research Fund, the Fondation ULB, ERANET Neuron Microkin, ERANET E-rare Euromicro and ERC-2013 ERC-2013-AG-340020.

Published
2018

4. MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Author

Douet, Julien, Corujo, David, Malinverni, Roberto, Renauld, Justine, Sansoni, Viola, Posavec Marjanović, Melanija, Cantarino, Neus, Valero, Vanesa, Mongelard, Fabien, Bouvet, Philippe, Imhof, Axel, Thiry, Marc, Buschbeck, Marcus, Buschbeck, Marc, Génétique, Reproduction et Développement (GReD), 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), Universitat Autònoma de Barcelona (UAB), The institute of cancer research [London], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille-Luminy (IBDML), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], 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), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Heterochromatin, [SDV]Life Sciences [q-bio], Biology, Methylation, Histones, 03 medical and health sciences, Histone H3, Histone H1, Histone variant, Histone H2A, Constitutive heterochromatin, Nucleosome, Histone code, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, Nuclear organization, Lamin Type B, Lysine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Hep G2 Cells, 030104 developmental biology, HEK293 Cells, DNA repeats, Heterochromatin protein 1, Cell Nucleolus, Protein Binding
Abstract

International audience; Genetic loss-of-function studies on development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by histone H3 trimethylated on K9 (H3K9me3). Loss of macroH2A leads to major defects in nuclear organization, including reduced nuclear circularity, disruption of nucleoli and a global loss of dense heterochromatin. Domains formed by DNA repeat sequences are disorganized, expanded and fragmented, and mildly re-expressed when depleted of macroH2A. At the molecular level, we find that macroH2A is required for the interaction of repeat sequences with the nucleostructural protein lamin B1. Taken together, our results argue that a major function of macroH2A histone variants is to link nucleosome composition to higher-order chromatin architecture.

Published
2017

5. Elevated Plasma Soluble ST2 Is Associated with Heart Failure Symptoms and Outcome in Aortic Stenosis

Author

Arnaud Ancion, Laurent Davin, Julien Magne, Luc Pierard, Nassim Bouznad, Christine Henri, Christophe Martinez, Cécile Oury, Patrizio Lancellotti, Laurence Servais, Raluca Elena Dulgheru, Alain Nchimi, Caroline Le Goff, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Service de cardiologie [Liège], CHU de Liège-Domaine Universitaire du Sart Tilman, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de cardiologie [CHU Limoges], CHU Limoges, GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Service de cardiologie, Centre Hospitalier Universitaire de Liège (CHU-Liège), Cardio-vascular diseases, and Clinical sciences

Subjects
Aortic valve, Male, medicine.medical_specialty, medicine.drug_class, lcsh:Medicine, Receptors, Cell Surface, 030204 cardiovascular system & hematology, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Natriuretic peptide, Humans, 030212 general & internal medicine, lcsh:Science, Aged, Aged, 80 and over, Heart Failure, Multidisciplinary, Ejection fraction, business.industry, lcsh:R, Aortic Valve Stenosis, Middle Aged, medicine.disease, Interleukin-1 Receptor-Like 1 Protein, Stenosis, medicine.anatomical_structure, Aortic valve stenosis, Heart failure, Cardiology, cardiovascular system, Biomarker (medicine), lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, medicine.symptom, business, Research Article
Abstract

International audience; B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is associated with symptomatic status and outcome in asymptomatic AS is unknown. sST2 and BNP levels were measured in 86 patients (74±13 years; 59 asymptomatic, 69%) with AS (23 ng/mL, AUC = 0.68, p

Published
2015

6. Structural and Functional Organization of Ribosomal Genes within the Mammalian Cell Nucleolus

Author

Derenzini, Massimo, Pasquinelli, Gianandrea, O'Donohue, Marie-Françoise, Ploton, Dominique, Thiry, Marc, O'Donohue, Marie-Francçoise, M Derenzini, G Pasquinelli, M-F O'Donohue, D Ploton, M Thiry, Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], and Université de Liège-C.H.U. Sart Tilman [Liège]

Subjects
0301 basic medicine, Histology, Transcription, Genetic, Nucleolus, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, DNA, Ribosomal, Ribosome, 03 medical and health sciences, chemistry.chemical_compound, RNA Precursors, Animals, Humans, Gene, Ribosomal DNA, Mammals, 030102 biochemistry & molecular biology, RNA, Ribosomal RNA, Chromatin, Cell biology, Microscopy, Electron, 030104 developmental biology, chemistry, RNA, Ribosomal, Nucleic Acid Conformation, Anatomy, Ribosomes, Cell Nucleolus, DNA
Abstract

International audience; Data on the in situ structural-functional organization of ribosomal genes in the mammalian cell nucleolus are reviewed here. Major findings on chromatin structure in situ come from investigations carried out using the Feulgen-like osmium ammine reaction as a highly specific electron-opaque DNA tracer. Intranucleolar chromatin shows three different levels of organization: compact clumps, fibers ranging from 11 to 30 nm, and loose agglomerates of extended DNA filaments. Both clumps and fibers of chromatin exhibit a nucleosomal organization that is lacking in the loose agglomerates of extended DNA filaments. In fact, these filaments constantly show a thickness of 2-3 nm, the same as a DNA double-helix molecule. The loose agglomerates of DNA filaments are located in the fibrillar centers, the interphase counterpart of metaphase NORs, therefore being constituted by ribosomal DNA. The extended, non-nucleosomal configuration of this rDNA has been shown to be independent of transcriptional activity and characterizes ribosome genes that are either transcribed or transcriptionally silent. Data reviewed are consistent with a model of control for ribosome gene activity that is not mediated by changes in chromatin structure. The presence of rDNA in mammalian cells always structurally ready for transcription might facilitate a more rapid adjustment of the ribosome production in response to the metabolic needs of the cell.

Published
2006

7. Electron Tomography of Metaphase Nucleolar Organizer Regions: Evidence for a Twisted-Loop Organization

Author

Laurent Héliot, Laurent Lucas, Marc Thiry, Hervé Kaplan, A. Beorchia, M. Menager, Dominique Ploton, Christophe Klein, Marie-Françoise O'Donohue, Martine Doco-Fenzy, Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine de Reims, Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), Université de Reims Champagne-Ardenne (URCA), UTAP, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], inconnu, and Inconnu

Subjects
Microscopy, Electron, Scanning Transmission, Models, Molecular, Chromosomal Proteins, Non-Histone, Protein Conformation, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, DNA, Ribosomal, KB Cells, Article, law.invention, Mice, 03 medical and health sciences, Confocal microscopy, law, Centromere, Image Processing, Computer-Assisted, Nucleolus Organizer Region, Tumor Cells, Cultured, Animals, Humans, Carcinoma, Ehrlich Tumor, Molecular Biology, Metaphase, 030304 developmental biology, 0303 health sciences, Microscopy, Confocal, 030302 biochemistry & molecular biology, Chromosome, Cell Biology, Chromatin, Cell biology, Electron tomography, Nucleic Acid Conformation, Chromatid, Leukemia, Erythroblastic, Acute, Nucleolus organizer region
Abstract

International audience; Metaphase nucleolar organizer regions (NORs), one of four types of chromosome bands, are located on human acrocentric chromosomes. They contain r-chromatin, i.e., ribosomal genes complexed with proteins such as upstream binding factor and RNA polymerase I, which are argyrophilic NOR proteins. Immunocytochemical and cytochemical labelings of these proteins were used to reveal r-chromatin in situ and to investigate its spatial organization within NORs by confocal microscopy and by electron tomography. For each labeling, confocal microscopy revealed small and large double-spotted NORs and crescent-shaped NORs. Their internal three-dimensional (3D) organization was studied by using electron tomography on specifically silver-stained NORs. The 3D reconstructions allow us to conclude that the argyrophilic NOR proteins are grouped as a fiber of 60-80 nm in diameter that constitutes either one part of a turn or two or three turns of a helix within small and large double-spotted NORs, respectively. Within crescent-shaped NORs, virtual slices reveal that the fiber constitutes several longitudinally twisted loops, grouped as two helical 250- to 300-nm coils, each centered on a nonargyrophilic axis of condensed chromatin. We propose a model of the 3D organization of r-chromatin within elongated NORs, in which loops are twisted and bent to constitute one basic chromatid coil.

Published
1997

8. Three-dimensional organization of active rRNA genes within the nucleolus

Author

Hervé Kaplan, Adrien Beorchia, Marie-Françoise O'Donohue, Marc Thiry, Thierry Cheutin, Marc Vandelaer, Dominique Ploton, Bruno Defever, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), UTAP, Faculté de Médecine de Reims, GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], and Université de Liège-C.H.U. Sart Tilman [Liège]

Subjects
Dense fibrillar component, Nucleolus, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Uridine Triphosphate, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, DNA, Ribosomal, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, RNA Polymerase I, RNA polymerase I, Humans, Gene, 030304 developmental biology, Nucleic Acid Synthesis Inhibitors, 0303 health sciences, biology, Deoxyadenosines, Models, Genetic, 030302 biochemistry & molecular biology, RNA, Genes, rRNA, Cell Biology, Ribosomal RNA, Molecular biology, Immunohistochemistry, Cell biology, chemistry, RNA, Ribosomal, biology.protein, Dactinomycin, Nucleic Acid Conformation, DNA polymerase I, DNA, Cell Nucleolus
Abstract

International audience; In this work, we have localized transcribing rRNA genes at the ultrastructural level and described their three-dimensional organization within the nucleolus by electron tomography. Isolated nucleoli, which exhibit a reduced transcriptional rate, were used to determine the sites of initial BrUTP incorporation (i.e. rRNA synthesis by the transcriptional machinery). Using pulse-chase experiments with BrUTP and an elongation inhibitor, cordycepin, it was possible to precisely localize the initial sites of BrUTP incorporation. Our data show that BrUTP incorporation initially takes place in the fibrillar centers and that elongating rRNAs rapidly enter the surrounding dense fibrillar component. Furthermore, we investigated the spatial arrangement of RNA polymerase I molecules within the whole volume of the fibrillar centers. Electron tomography was performed on thick sections of cells that had been labeled with anti-RNA polymerase I antibodies prior to embedding. Detailed tomographic analyses revealed that RNA polymerase I molecules are mainly localized within discrete clusters. In each of them, RNA polymerase I molecules were grouped as several coils, 60 nm in diameter. Overall, these findings have allowed us to propose a model for the three-dimensional organization of transcribing rDNA genes within the nucleolus.

Published
2002

9. Dynamics and three-dimensional localization of ribosomal RNA within the nucleolus

Author

Marc Thiry, Marie-Françoise O'Donohue, Dominique Ploton, Thierry Cheutin, Hervé Kaplan, GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R) [Liège], Université de Liège-C.H.U. Sart Tilman [Liège], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Faculté de Médecine de Reims

Subjects
Cytoplasm, Nucleolus, [SDV]Life Sciences [q-bio], Ribosome biogenesis, Uridine Triphosphate, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Humans, RNA, Neoplasm, Microscopy, Immunoelectron, Molecular Biology, 030304 developmental biology, 0303 health sciences, Microscopy, Confocal, Dynamics (mechanics), RNA, Ribosomal RNA, Cell biology, Microscopy, Fluorescence, RNA, Ribosomal, 030220 oncology & carcinogenesis, Radial flow, Electron microscope, Cell Nucleolus, HeLa Cells, Research Article
Abstract

International audience; Although rRNA synthesis, maturation, and assembly into preribosomal particles occur within the nucleolus, the route taken by pre-rRNAs from their synthetic sites toward the cytoplasm remains largely unexplored. Here, we employed a nondestructive method for the incorporation of BrUTP into the RNA of living cells. By using pulse-chase experiments, three-dimensional image reconstructions of confocal optical sections, and electron microscopy analysis of ultrathin sections, we were able to describe topological and spatial dynamics of rRNAs within the nucleolus. We identified the precise location and the volumic organization of four typical subdomains, in which rRNAs are successively moving towards the nucleolar periphery during their synthesis and processing steps. The incorporation of BrUTP takes place simultaneously within several tiny spheres, centered on the fibrillar centers. Then, the structures containing the newly synthesized RNAs enlarge and appear as compact ringlets disposed around the fibrillar centers. Later, they form hollow spheres surrounding the latter components and begin to fuse together. Finally, these structures widen and form large rings reaching the limits of the nucleoli. These results clearly show that the transport of pre-rRNAs within the nucleolus does not occur randomly, but appears as a radial flow starting from the fibrillar centers that form concentric rings, which finally fuse together as they progress toward the nucleolar periphery.

Published
2000

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