Mouse Mbnl2 Knockout Project (CRISPR/Cas9)
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MBNL1 Regulates Essential Alternative RNA Splicing Patterns in MLL-Rearranged Leukemia
ARTICLE https://doi.org/10.1038/s41467-020-15733-8 OPEN MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia Svetlana S. Itskovich1,9, Arun Gurunathan 2,9, Jason Clark 1, Matthew Burwinkel1, Mark Wunderlich3, Mikaela R. Berger4, Aishwarya Kulkarni5,6, Kashish Chetal6, Meenakshi Venkatasubramanian5,6, ✉ Nathan Salomonis 6,7, Ashish R. Kumar 1,7 & Lynn H. Lee 7,8 Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, 1234567890():,; targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.Wefinally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins. 1 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 2 Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
Identification of Protein Features Encoded by Alternative Exons Using Exon Ontology
Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Resource Identification of protein features encoded by alternative exons using Exon Ontology Léon-Charles Tranchevent,1 Fabien Aubé,1 Louis Dulaurier,1 Clara Benoit-Pilven,1 Amandine Rey,1 Arnaud Poret,1 Emilie Chautard,2 Hussein Mortada,1 François-Olivier Desmet,1 Fatima Zahra Chakrama,1 Maira Alejandra Moreno-Garcia,1 Evelyne Goillot,3 Stéphane Janczarski,1 Franck Mortreux,1 Cyril F. Bourgeois,1,4 and Didier Auboeuf1,4 1Université Lyon 1, ENS de Lyon, CNRS UMR 5239, INSERM U1210, Laboratory of Biology and Modelling of the Cell, F-69007, Lyon, France; 2Laboratoire de Biométrie et Biologie Évolutive, Université Lyon 1, UMR CNRS 5558, INRIA Erable, Villeurbanne, F-69622, France; 3Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Lyon 1, Lyon, F-69007 France Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing var- iation in physiological- or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named Exon Ontology, based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encod- ed protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splic- ing. -
ID AKI Vs Control Fold Change P Value Symbol Entrez Gene Name *In
ID AKI vs control P value Symbol Entrez Gene Name *In case of multiple probesets per gene, one with the highest fold change was selected. Fold Change 208083_s_at 7.88 0.000932 ITGB6 integrin, beta 6 202376_at 6.12 0.000518 SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 1553575_at 5.62 0.0033 MT-ND6 NADH dehydrogenase, subunit 6 (complex I) 212768_s_at 5.50 0.000896 OLFM4 olfactomedin 4 206157_at 5.26 0.00177 PTX3 pentraxin 3, long 212531_at 4.26 0.00405 LCN2 lipocalin 2 215646_s_at 4.13 0.00408 VCAN versican 202018_s_at 4.12 0.0318 LTF lactotransferrin 203021_at 4.05 0.0129 SLPI secretory leukocyte peptidase inhibitor 222486_s_at 4.03 0.000329 ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 1552439_s_at 3.82 0.000714 MEGF11 multiple EGF-like-domains 11 210602_s_at 3.74 0.000408 CDH6 cadherin 6, type 2, K-cadherin (fetal kidney) 229947_at 3.62 0.00843 PI15 peptidase inhibitor 15 204006_s_at 3.39 0.00241 FCGR3A Fc fragment of IgG, low affinity IIIa, receptor (CD16a) 202238_s_at 3.29 0.00492 NNMT nicotinamide N-methyltransferase 202917_s_at 3.20 0.00369 S100A8 S100 calcium binding protein A8 215223_s_at 3.17 0.000516 SOD2 superoxide dismutase 2, mitochondrial 204627_s_at 3.04 0.00619 ITGB3 integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 223217_s_at 2.99 0.00397 NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 231067_s_at 2.97 0.00681 AKAP12 A kinase (PRKA) anchor protein 12 224917_at 2.94 0.00256 VMP1/ mir-21likely ortholog -
Towards Personalized Medicine in Psychiatry: Focus on Suicide
TOWARDS PERSONALIZED MEDICINE IN PSYCHIATRY: FOCUS ON SUICIDE Daniel F. Levey Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Program of Medical Neuroscience, Indiana University April 2017 ii Accepted by the Graduate Faculty, Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Andrew J. Saykin, Psy. D. - Chair ___________________________ Alan F. Breier, M.D. Doctoral Committee Gerry S. Oxford, Ph.D. December 13, 2016 Anantha Shekhar, M.D., Ph.D. Alexander B. Niculescu III, M.D., Ph.D. iii Dedication This work is dedicated to all those who suffer, whether their pain is physical or psychological. iv Acknowledgements The work I have done over the last several years would not have been possible without the contributions of many people. I first need to thank my terrific mentor and PI, Dr. Alexander Niculescu. He has continuously given me advice and opportunities over the years even as he has suffered through my many mistakes, and I greatly appreciate his patience. The incredible passion he brings to his work every single day has been inspirational. It has been an at times painful but often exhilarating 5 years. I need to thank Helen Le-Niculescu for being a wonderful colleague and mentor. I learned a lot about organization and presentation working alongside her, and her tireless work ethic was an excellent example for a new graduate student. I had the pleasure of working with a number of great people over the years. Mikias Ayalew showed me the ropes of the lab and began my understanding of the power of algorithms. -
Parental-To-Embryo Switch of Chromosome Organization in Early
Parental-to-embryo switch of chromosome organization in early embryogenesis Samuel Collombet, Noemie Ranisavljevic, Takashi Nagano, Csilla Varnai, Tarak Shisode, Wing Leung, Tristan Piolot, Rafael Galupa, Maud Borensztein, Nicolas Servant, et al. To cite this version: Samuel Collombet, Noemie Ranisavljevic, Takashi Nagano, Csilla Varnai, Tarak Shisode, et al.. Parental-to-embryo switch of chromosome organization in early embryogenesis. Nature, Nature Pub- lishing Group, 2020, 580, pp.142 - 146. 10.1038/s41586-020-2125-z. hal-03027197 HAL Id: hal-03027197 https://hal.archives-ouvertes.fr/hal-03027197 Submitted on 27 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article Parental-to-embryo switch of chromosome organization in early embryogenesis https://doi.org/10.1038/s41586-020-2125-z Samuel Collombet1,2,10, Noémie Ranisavljevic1,3,10, Takashi Nagano4,9,10, Csilla Varnai4,5, Tarak Shisode6, Wing Leung4,9, Tristan Piolot1, Rafael Galupa1,2, Maud Borensztein1, Received: 3 April 2019 Nicolas Servant7, Peter Fraser4,8,11 ✉, Katia Ancelin1,11 ✉ & Edith Heard1,2,11 ✉ Accepted: 16 January 2020 Published online: 25 March 2020 Paternal and maternal epigenomes undergo marked changes after fertilization1. Recent Check for updates epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifcations2–4 and diferences in chromosome organization and accessibility, both in gametes5–8 and after fertilization5,8–10. -
Muscleblind-Like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy
Neuron Article Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy Konstantinos Charizanis,1 Kuang-Yung Lee,1,4 Ranjan Batra,1 Marianne Goodwin,1 Chaolin Zhang,5 Yuan Yuan,5 Lily Shiue,6 Melissa Cline,6 Marina M. Scotti,1 Guangbin Xia,2 Ashok Kumar,3 Tetsuo Ashizawa,2 H. Brent Clark,7 Takashi Kimura,8 Masanori P. Takahashi,9 Harutoshi Fujimura,10 Kenji Jinnai,11 Hiroo Yoshikawa,8 Ma´ rio Gomes-Pereira,12 Genevie` ve Gourdon,12 Noriaki Sakai,13 Seiji Nishino,13 Thomas C. Foster,3 Manuel Ares, Jr.,6 Robert B. Darnell,5 and Maurice S. Swanson1,* 1Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics 2Department of Neurology 3Department of Neuroscience University of Florida, College of Medicine, Gainesville, FL 32610, USA 4Department of Neurology, Chang Gung Memorial Hospital, Keelung 204, Taiwan 5Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA 6Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA 95064, USA 7Departments of Laboratory Medicine and Pathology, Neurology, and Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA 8Division of Neurology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan 9Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan 10Department of Neurology, National Hospital Organization, Toneyama Hospital, Osaka -
Dynamics of Alternative Splicing During Somatic Cell Reprogramming Reveals Functions for RNA-Binding Proteins CPSF3, Hnrnp UL1 and TIA1
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.299867; this version posted September 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Dynamics of alternative splicing during somatic cell reprogramming reveals functions for RNA-binding proteins CPSF3, hnRNP UL1 and TIA1 Claudia Vivori1,2, Panagiotis Papasaikas1,#, Ralph Stadhouders1,##, Bruno Di Stefano1,%, Clara Berenguer Balaguer1,%%, Serena Generoso1,2, Anna Mallol1, José Luis Sardina1,%%, Bernhard Payer1,2, Thomas Graf1,2 and Juan Valcárcel1,2,3* 1 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain 2 Universitat Pompeu Fabra (UPF), Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain 3 Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain * Correspondence to [email protected] # Current address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66 / Swiss Institute of Bioinformatics, 4058 Basel, Switzerland ## Current address: Departments of Pulmonary Medicine and Cell Biology, Erasmus MC, Rotterdam, The Netherlands % Current address: Department of Molecular Biology, Massachusetts General Hospital / Center for Regenera- tive Medicine / Center for Cancer Research, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA / Department of Stem Cell and Regenerative Biology / Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA %% Current address: Josep Carreras Leukaemia Research Institute, Carretera de Can Ruti, Camí de les Escoles, s/n, 08916 Badalona, Spain 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.17.299867; this version posted September 18, 2020. -
Network Pharmacology-Based Approach Uncovers the Mechanism of Guanxinning Tablet for Treating Thrombus by Mapks Signal Pathway
ORIGINAL RESEARCH published: 13 May 2020 doi: 10.3389/fphar.2020.00652 Network Pharmacology-Based Approach Uncovers the Mechanism of GuanXinNing Tablet for Treating Thrombus by MAPKs Signal Pathway † † Mu-Lan Wang 1,2 , Qin-Qin Yang 1,3 , Xu-Hui Ying 2, Yuan-Yuan Li 1, Yang-Sheng Wu 1, Qi-Yang Shou 1, Quan-Xin Ma 1, Zi-Wei Zhu 2 and Min-Li Chen 1* 1 Academy of Chinese Medicine & Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou, China, 2 The Department of Medicine, Chiatai Qingchunbao Pharmaceutical Co., Ltd., Hangzhou, China, 3 Department of Experimental Animals, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China Edited by: Background: GuanXinNing tablet (GXNT), a traditional Chinese patent medicine, has Jianxun Liu, been found to have remarkable antithrombotic effects and can effectively inhibit pro- China Academy of Chinese Medical Sciences, China thrombotic factors in previous studies. However, the mechanism of its antithrombotic Reviewed by: effects remains little known. Songxiao Xu, fi fi Artron BioResearch Inc., Canada Methods: In this study, we rst determined and identi ed the sources of each main Yi Ding, compound in GXNT using liquid chromatography-mass spectrometry (LC-MS). Through Fourth Military Medical the approach of network pharmacology, we predicted the action targets of the active University, China Yunyao Jiang, components, mapped the target genes related to thrombus, and obtained potential Tsinghua University, China antithrombotic targets for active ingredients. We then performed gene ontology (GO) *Correspondence: enrichment analyses and KEGG signaling pathway analyses for the action targets, and Min-Li Chen – – – [email protected] constructed networks of active component target and active component target †These authors have contributed pathway for GXNT. -
Supplementary Material Peptide-Conjugated Oligonucleotides Evoke Long-Lasting Myotonic Dystrophy Correction in Patient-Derived C
Supplementary material Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice Arnaud F. Klein1†, Miguel A. Varela2,3,4†, Ludovic Arandel1, Ashling Holland2,3,4, Naira Naouar1, Andrey Arzumanov2,5, David Seoane2,3,4, Lucile Revillod1, Guillaume Bassez1, Arnaud Ferry1,6, Dominic Jauvin7, Genevieve Gourdon1, Jack Puymirat7, Michael J. Gait5, Denis Furling1#* & Matthew J. A. Wood2,3,4#* 1Sorbonne Université, Inserm, Association Institut de Myologie, Centre de Recherche en Myologie, CRM, F-75013 Paris, France 2Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK 3Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, UK 4MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK 5Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK 6Sorbonne Paris Cité, Université Paris Descartes, F-75005 Paris, France 7Unit of Human Genetics, Hôpital de l'Enfant-Jésus, CHU Research Center, QC, Canada † These authors contributed equally to the work # These authors shared co-last authorship Methods Synthesis of Peptide-PMO Conjugates. Pip6a Ac-(RXRRBRRXRYQFLIRXRBRXRB)-CO OH was synthesized and conjugated to PMO as described previously (1). The PMO sequence targeting CUG expanded repeats (5′-CAGCAGCAGCAGCAGCAGCAG-3′) and PMO control reverse (5′-GACGACGACGACGACGACGAC-3′) were purchased from Gene Tools LLC. Animal model and ASO injections. Experiments were carried out in the “Centre d’études fonctionnelles” (Faculté de Médecine Sorbonne University) according to French legislation and Ethics committee approval (#1760-2015091512001083v6). HSA-LR mice are gift from Pr. Thornton. The intravenous injections were performed by single or multiple administrations via the tail vein in mice of 5 to 8 weeks of age. -
A Computational Analysis of Alternative Splicing Across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events
International Journal of Molecular Sciences Article A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events Rukeia El-Athman 1,2, Dora Knezevic 1,2, Luise Fuhr 1,2 and Angela Relógio 1,2,* 1 Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany 2 Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany * Correspondence: [email protected] Received: 9 July 2019; Accepted: 10 August 2019; Published: 15 August 2019 Abstract: Mounting evidence points to a role of the circadian clock in the temporal regulation of post-transcriptional processes in mammals, including alternative splicing (AS). In this study, we carried out a computational analysis of circadian and ultradian rhythms on the transcriptome level to characterise the landscape of rhythmic AS events in published datasets covering 76 tissues from mouse and olive baboon. Splicing-related genes with 24-h rhythmic expression patterns showed a bimodal distribution of peak phases across tissues and species, indicating that they might be controlled by the circadian clock. On the output level, we identified putative oscillating AS events in murine microarray data and pairs of differentially rhythmic splice isoforms of the same gene in baboon RNA-seq data that peaked at opposing times of the day and included oncogenes and tumour suppressors. We further explored these findings using a new circadian RNA-seq dataset of human colorectal cancer cell lines. -
Muscleblind-Like 2 Controls the Hypoxia Response of Cancer Cells
Downloaded from rnajournal.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Muscleblind-like 2 controls the hypoxia response of cancer cells Sandra Fischer1, Antonella Di Liddo2, Katarzyna Taylor3, Jamina S. Gerhardus1, Krzysztof Sobczak3, Kathi Zarnack2 and Julia E. Weigand1,* 1 Department of Biology, Technical University of Darmstadt, Darmstadt, 64287, Germany 2 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, 60438, Germany 3 Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, 61-614, Poland * Correspondence should be addressed to [email protected] Running Title: MBNL2 drives hypoxia adaptation Keywords: hypoxia, cancer, MBNL2, HIF target genes, alternative splicing Abstract Hypoxia is a hallmark of solid cancers, supporting proliferation, angiogenesis and escape from apoptosis. There is still limited understanding of how cancer cells adapt to hypoxic conditions and survive. We analyzed transcriptome changes of human lung and breast cancer cells under chronic hypoxia. Hypoxia induced highly concordant changes in transcript abundance, but divergent splicing responses, underlining the cell type-specificity of alternative splicing programs. While RNA-binding proteins were predominantly reduced, hypoxia specifically induced muscleblind-like protein 2 (MBNL2). Strikingly, MBNL2 induction was critical for hypoxia adaptation by controlling the transcript abundance of hypoxia response genes, such as vascular endothelial growth factor A (VEGFA). MBNL2 depletion reduced the proliferation and migration of cancer cells, demonstrating an important role of MBNL2 as cancer driver. Hypoxia control is specific for MBNL2 and not shared by its paralog MBNL1. Thus, our study revealed MBNL2 as central mediator of cancer cell responses to hypoxia, regulating the expression and alternative splicing of hypoxia-induced genes.