Aberrant Splicing in B-Cell Acute Lymphoblastic Leukemia
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Large-Scale Analysis of Genome and Transcriptome Alterations in Multiple Tumors Unveils Novel Cancer-Relevant Splicing Networks
Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén,1,5 Babita Singh,1,5 Belén Miñana,1,2 Amadís Pagès,1 Francesca Mateo,3 Miguel Angel Pujana,3 Juan Valcárcel,1,2,4 and Eduardo Eyras1,4 1Universitat Pompeu Fabra, E08003 Barcelona, Spain; 2Centre for Genomic Regulation, E08003 Barcelona, Spain; 3Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L’Hospitalet del Llobregat, Spain; 4Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We system- atically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alter- natively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferen- tiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome am- plification in nontumorigenic mammary epithelial cells. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Downloaded from the TCGA Data Portal ( Data.Nci.Nih.Gov/Tcga/) (Supplemental Table S1)
bioRxiv preprint doi: https://doi.org/10.1101/023010; this version posted February 11, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks Endre Sebestyén1,*, Babita Singh1,*, Belén Miñana1,2, Amadís Pagès1, Francesca Mateo3, Miguel Angel Pujana3, Juan Valcárcel1,2,4, Eduardo Eyras1,4,5 1Universitat Pompeu Fabra, Dr. Aiguader 88, E08003 Barcelona, Spain 2Centre for Genomic Regulation, Dr. Aiguader 88, E08003 Barcelona, Spain 3Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L’Hospitalet del Llobregat, Spain. 4Catalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, E08010 Barcelona, Spain *Equal contribution 5Correspondence to: [email protected] Keywords: alternative splicing, RNA binding proteins, splicing networks, cancer 1 bioRxiv preprint doi: https://doi.org/10.1101/023010; this version posted February 11, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. -
1 Title 1 Loss of PABPC1 Is Compensated by Elevated PABPC4
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.07.430165; this version posted February 15, 2021. 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. 1 1 Title 2 Loss of PABPC1 is compensated by elevated PABPC4 and correlates with transcriptome 3 changes 4 5 Jingwei Xie1, 2, Xiaoyu Wei1, Yu Chen1 6 7 1 Department of Biochemistry and Groupe de recherche axé sur la structure des 8 protéines, McGill University, Montreal, Quebec H3G 0B1, Canada 9 10 2 To whom correspondence should be addressed: Dept. of Biochemistry, McGill 11 University, Montreal, QC H3G 0B1, Canada. E-mail: [email protected]. 12 13 14 15 Abstract 16 Cytoplasmic poly(A) binding protein (PABP) is an essential translation factor that binds to 17 the 3' tail of mRNAs to promote translation and regulate mRNA stability. PABPC1 is the 18 most abundant of several PABP isoforms that exist in mammals. Here, we used the 19 CRISPR/Cas genome editing system to shift the isoform composition in HEK293 cells. 20 Disruption of PABPC1 elevated PABPC4 levels. Transcriptome analysis revealed that the 21 shift in the dominant PABP isoform was correlated with changes in key transcriptional 22 regulators. This study provides insight into understanding the role of PABP isoforms in 23 development and differentiation. 24 Keywords 25 PABPC1, PABPC4, c-Myc 26 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.07.430165; this version posted February 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins
Biomolecules 2015, 5, 1441-1466; doi:10.3390/biom5031441 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Article Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins Rebecca Bish 1,†, Nerea Cuevas-Polo 1,†, Zhe Cheng 1, Dolores Hambardzumyan 2, Mathias Munschauer 3, Markus Landthaler 3 and Christine Vogel 1,* 1 Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, USA; E-Mails: [email protected] (R.B.); [email protected] (N.C.-P.); [email protected] (Z.C.) 2 The Cleveland Clinic, Department of Neurosciences, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA; E-Mail: [email protected] 3 RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Robert-Rössle-Str. 10, Berlin 13092, Germany; E-Mails: [email protected] (M.M.); [email protected] (M.L.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-212-998-3976; Fax: +1-212-995-4015. Academic Editor: André P. Gerber Received: 10 May 2015 / Accepted: 15 June 2015 / Published: 15 July 2015 Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. -
This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Expression and subcellular localisation of poly(A)-binding proteins Hannah Burgess PhD The University of Edinburgh 2010 Abstract Poly(A)-binding proteins (PABPs) are important regulators of mRNA translation and stability. In mammals four cytoplasmic PABPs with a similar domain structure have been described - PABP1, tPABP, PABP4 and ePABP. The vast majority of research on PABP mechanism, function and sub-cellular localisation is however limited to PABP1 and little published work has explored the expression of PABP proteins. Here, I examine the tissue distribution of PABP1 and PABP4 in mouse and show that both proteins differ markedly in their expression at both the tissue and cellular level, contradicting the widespread perception that PABP1 is ubiquitously expressed. PABP4 is shown to be widely expressed though with an expression pattern distinct from PABP1, and thus may have a biological function in many tissues. -
DIPPER, a Spatiotemporal Proteomics Atlas of Human Intervertebral Discs
TOOLS AND RESOURCES DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics Vivian Tam1,2†, Peikai Chen1†‡, Anita Yee1, Nestor Solis3, Theo Klein3§, Mateusz Kudelko1, Rakesh Sharma4, Wilson CW Chan1,2,5, Christopher M Overall3, Lisbet Haglund6, Pak C Sham7, Kathryn Song Eng Cheah1, Danny Chan1,2* 1School of Biomedical Sciences, , The University of Hong Kong, Hong Kong; 2The University of Hong Kong Shenzhen of Research Institute and Innovation (HKU-SIRI), Shenzhen, China; 3Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, Canada; 4Proteomics and Metabolomics Core Facility, The University of Hong Kong, Hong Kong; 5Department of Orthopaedics Surgery and Traumatology, HKU-Shenzhen Hospital, Shenzhen, China; 6Department of Surgery, McGill University, Montreal, Canada; 7Centre for PanorOmic Sciences (CPOS), The University of Hong Kong, Hong Kong Abstract The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity *For correspondence: and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising [email protected] 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key †These authors contributed directional trends spanning the lateral and anteroposterior axes were derived from high-resolution equally to this work spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific Present address: ‡Department profiles of regulatory activities -
Characterization of HNRNPA1 Mutations Defines Diversity in Pathogenic Mechanisms and Clinical Presentation
Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation Danique Beijer, … , J. Paul Taylor, Jonathan Baets JCI Insight. 2021;6(14):e148363. https://doi.org/10.1172/jci.insight.148363. Research Article Genetics Neuroscience Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro- )degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes. -
Analysis of Hnrnpa1, A2/B1, and A3 Genes in Patients with Amyotrophic Lateral Sclerosis
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Neurobiol Manuscript Author Aging. Author Manuscript Author manuscript; available in PMC 2019 June 25. Published in final edited form as: Neurobiol Aging. 2013 November ; 34(11): 2695.e11–2695.e12. doi:10.1016/j.neurobiolaging. 2013.05.025. Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis Daniela Calinia, Lucia Corradob, Roberto Del Boc,d, Stella Gagliardie, Viviana Pensatof, Federico Verdea,c, Stefania Cortic,d, Letizia Mazzinig, Pamela Milanie, Barbara Castellottif, Cinzia Bertolinh, Gianni Sorarùi, Cristina Ceredae, Giacomo P. Comic,d, Sandra D’Alfonsob, Cinzia Gelleraf, Nicola Ticozzia,c, John E. Landersj, Antonia Rattia,c,*, Vincenzo Silania,c, and The SLAGEN Consortium aDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy bDepartment of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, “A. Avogadro” University, Via Solaroli 17, 28100 Novara, Italy cDipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, “Dino Ferrari” Centre, Università degli Studi di Milano, Via Sforza 35, 20122 Milan, Italy dIRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, Via Sforza 35, 20122 Milan, Italy eLaboratory of Experimental Neurobiology, IRCCS National Neurological Institute “C. Mondino”, Via Mondino 2, 27100 Pavia, Italy fUnit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto -
Multiple Sclerosis-Associated Hnrnpa1 Mutations Alter Hnrnpa1 Dynamics and Influence Stress Granule Formation
International Journal of Molecular Sciences Article Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation Joseph-Patrick W. E. Clarke 1,2,* , Patricia A. Thibault 2,3, Hannah E. Salapa 2,3 , David E. Kim 4, Catherine Hutchinson 2,3 and Michael C. Levin 1,2,3,4,* 1 Department of Health Sciences, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 2 Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada; [email protected] (P.A.T.); [email protected] (H.E.S.); [email protected] (C.H.) 3 Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada 4 Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] * Correspondence: [email protected] (J.-P.W.E.C.); [email protected] (M.C.L.); Tel.: +1-306-6558 (M.C.L.) Abstract: Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Citation: Clarke, J.-P.W.E.; Thibault, Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis- P.A.; Salapa, H.E.; Kim, D.E.; associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress Hutchinson, C.; Levin, M.C. -
Solution Structure of the Two RNA Recognition Motifs of Hnrnp A1
Solution structure of the two RNA recognition motifs of hnRNP A1 using segmental isotope labeling: how the relative orientation between RRMs influences the nucleic acid binding topology. Pierre Barraud, Frédéric H-T Allain To cite this version: Pierre Barraud, Frédéric H-T Allain. Solution structure of the two RNA recognition motifs of hnRNP A1 using segmental isotope labeling: how the relative orientation between RRMs influences the nucleic acid binding topology.. Journal of Biomolecular NMR, Springer Verlag, 2013, 55 (1), pp.119-38. 10.1007/s10858-012-9696-4. hal-00782205 HAL Id: hal-00782205 https://hal.archives-ouvertes.fr/hal-00782205 Submitted on 29 Jan 2013 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. Solution structure of the two RNA recognition motifs of hnRNP A1 using segmental isotope labeling: how the relative orientation between RRMs influences the nucleic acid binding topology Pierre Barraud & Frédéric H.-T. Allain† Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zürich, Switzerland † Corresponding author: FH-T Allain, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, CH-8093 Zürich, Switzerland. Tel.: +41 44 633 3940, Fax: +41 44 633 1294. -
Structural and Functional Studies of Mrna Stability Regulators
Research Collection Doctoral Thesis Structural and Functional Studies of mRNA Stability Regulators Author(s): Ripin, Nina Publication Date: 2018-11 Permanent Link: https://doi.org/10.3929/ethz-b-000303696 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 25327 Structural and functional studies of mRNA stability regulators A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZÜRICH (Dr. sc. ETH Zürich) presented by NINA RIPIN Diplom-Biochemikerin, Goethe University, Frankfurt, Germany Born on 06.08.1986 citizen of Germany accepted on the recommendation of Prof. Dr. Frédéric Allain Prof. Dr. Stefanie Jonas Prof. Dr. Michael Sattler Prof. Dr. Witold Filipowicz 2018 “Success consists of going from failure to failure without loss of enthusiasm.” Winston Churchill Summary Posttranscriptional gene regulation (PTGR) is the process by which every step of the life cycle of an mRNA following transcription – maturation, transport, translation, subcellular localization and decay - is tightly regulated. This is accomplished by a complex network of multiple RNA binding proteins (RNPs) binding to several specific mRNA elements. Such cis-acting elements are or can be found within the 5’ cap, the 5’ untranslated region (UTR), the open reading frame (ORF), the 3’UTR and the poly(A) tail at the 3’ end of the mRNA. Adenylate-uridylate-rich elements (AU-rich elements; AREs) are heavily investigated regulatory cis- acting elements within 3’untranslated regions (3’UTRs). These are found in short-lived mRNAs and function as a signal for rapid degradation.