DOCSLIB.ORG

TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer A Prominent Couple Citation for published version (APA): Ratz, L. (2017). A Prominent Couple: the TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer . Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20171215lr Document status and date: Published: 01/01/2017 DOI: 10.26481/dis.20171215lr Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 03 Oct. 2021 A Prominent Couple The TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer A Prominent Couple – The TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer Leonie Ratz ISBN 978 94 6159 776 2 UMP Cover design and layout by Leonie Ratz UNIVERSITAIRE Printed by Datawyse | Universitaire Pers Maastricht PERS MAASTRICHT Copyright © Leonie Ratz, Cologne 2017 All rights reserved. No parts of this thesis may be reproduced, stored or transmitted in any form or by any means without prior written permission of the author. Cover illustration: collection of silhouettes of men (from shutterstock.inc) A Prominent Couple The TMPRSS2:ERG Gene Fusion in Aggressive Prostate Cancer DISSERTATION to obtain the degree of Doctor at Maastricht University, on the authority of the Rector Magnificus, Prof. Dr. Rianne M. Letschert in accordance with the decision of the Board of Deans, to be defended in public on Friday, 15th of December 2017, at 13:30 hours by Leonie Ratz born on 23rd of March 1987 in Cologne SUPERVISORS Prof. Dr. F. C. S. Ramaekers Prof. Dr. H. Sültmann (German Cancer Research Center and National Center of Tumor Diseases, Heidelberg) CO-SUPERVISORS Privatdozentin Dr. S. M. Klauck (German Cancer Research Center, Heidelberg) Prof. Dr. P. Altevogt (German Cancer Research Center, Heidelberg) ASSESSMENT COMMITTEE Prof. Dr. M. van Engeland (chair) Prof. Dr. J. Schalken (Radboud University Medical Center, Nijmegen) Prof. Dr. S. Pahernik (Nuremberg General Hospital, Paracelsus Medical University, Nuremberg) Prof. Dr. M. Vooijs FUNDING This project was supported through intramural funding by the German Cancer Research Center. CONTENTS List of abbreviations 6 General introduction 9 Chapter 1 The biology of aggressive prostate cancer: Implications for innovative diagnostics and therapy 17 Chapter 2 TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells 39 Chapter 3 TMPRSS2:ERG overexpression induces changes in the epigenetic signature of human prostate cancer cells: Hypomethylation correlates with upregulation of FZD4 and HLA-DMB 73 Chapter 4 INSM1 induces a neuroendocrine phenotype in prostate cancer cells 107 Chapter 5 General discussion 169 Valorisation 177 Summary 181 Nederlandse samenvatting 187 Deutsche Zusammenfassung 193 Acknowledgements 199 Curriculum vitae 201 Publication list 202 LIST OF ABBREVIATIONS ACPP acid phosphatase, prostate ADT androgen deprivation therapy AKT AKT serine/threonine kinase 1 ALK1 activin receptor like kinase 1 AMACR alpha-methylacyl-CoA racemase AR androgen receptor AR-V7 androgen receptor splice variant 7 ASCL1 achaete-scute homolog 1 BAMBI BMP and activin membrane-bound inhibitor BCA bicinchoninic acid BMP bone morphogenetic protein bp base pair BPH benign prostate hyperplasia BSA bovine serum albumin CD24 cluster of differentiation 24 CDH1 E-cadherin CDH2 N-cadherin CDK1 cyclin-dependent kinase 1 cDNA complementary DNA CFU colony forming units CHD1 chromodomain helicase DNA binding protein 1 CHGA and B chromogranin A and B CK cytokeratin CNA Copy number alteration Cp crossing point CRPC castration-resistant prostate cancer CTC circulating tumor cell DHT dihydrotestosterone DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DNase deoxyribunuclease DNMT DNA methyltransferase Dox doxycycline EGFR epidermal growth factor receptor EMT epithelial-to-mesenchymal transition ERG V-ets erythroblastosis virus E26 homolog (avian) ERK2 extracellular signal-regulated kinases, alias of MAPK1 Ev empty vector 6 FC fold change FN1 fibronectin 1 FPKM fragments per kilobase of exon per million fragments mapped FZD4 frizzled 4 GAPDH glyceraldehyde-3-phosphate dehydrogenase GO gene ontology HGPIN high-grade prostatic intraepithelial neoplasia HLA-DMB major histocompatibility complex, class II, DM beta ICGC-EOPC International Cancer Genome Consortium-Early Onset PCa project ID1 and 2 inhibitor of differentiation (1 and 2) IGP NGFN IG Prostate Cancer project INSM1 insulinoma associated-1 IPA Ingenuity Pathway Analysis JNK c-Jun N-terminal kinases L1CAM L1 cell adhesion molecule LRP5 and 6 low-density lipoprotein receptor-related protein 5 and 6 MAPK mitogen-activated protein kinase MET mesenchymal-to-epithelial transition miR micro-RNA MMP matrix metalloproteinase MSMB microseminoprotein beta MYCN N-myc proto-oncogene NCAM neuronal cell adhesion molecule NED neuroendocrine differentiation NEPC neuroendocrine prostate cancer NSE neuron specific enolase ORF open reading frame p38 alias of MAPK14, mitogen-activated protein kinase 14 pAKT phospho-AKT PAP prostatic acid phosphatase PCa prostate cancer PI3K phosphatidylinositol 3-kinase PIN prostatic intraepithelial neoplasia PLA1A phospholipase A1 member A PLAT plasminogen activator, tissue type p-p38 phospho-p38 PSA prostate specific antigen pSMAD phospho-SMAD qPCR quantitative reverse transcription PCR RELN reelin 7 REST RE-1 silencing transcription factor/neuron-restrictive silencer factor (NRSF) rhALK1 recombinant decoy receptor ALK1 rhFZD4 recombinant decoy receptor FZD4 RPKM reads per kilobase per million mapped reads RT-PCR reverse transcription PCR SCG3 secretogranin III siRNA small interfering RNA SLC45A3 solute carrier family 45 member 3 SMAD SMAD family protein SNAI2 snail family transcriptional repressor 2 SYP synaptophysin TCF7L2 T cell factor/lymphoid enhancer 2 TCF/LEF-1 transcription factor/lymphoid enhancer binding factor 1 TCGA The Cancer Genome Atlas TDRD1 tudor domain containing 1 T/E TMPRSS2:ERG TGF-β transforming growth factor beta TGFB1 and 2 TGF-β 1 and 2 TMPRSS2 transmembrane protease, serine 2 TUBB3 tubulin beta 3 VIM vimentin VTN vitronectin WNT wingless-type family member ZEB1 zinc finger E-box binding homeobox 1 8 General introduction 9 THE EPIDEMIOLOGY OF PROSTATE CANCER Prostate cancer (PCa) is the most prevalent non-cutaneous malignancy accounting for 15% of the cancers diagnosed in men [1]. It is the second leading cause of cancer- related death in men in Western countries with 417,000 new cases and 92,000 deaths in 2012 in Europe [1, 2]. Only few risk determinants for the development of PCa have been defined, such as increasing age, ethnic or geographical origin, and family history, while the influence of lifestyle factors is less well-established [3-5]. Increasing age is by far the most important risk factor. Only 30% of all cases are diagnosed under the age of 65 years in the US [6]. The 10-years risk to develop PCa for men aged 30 years is 0.01%, increases to 4.77% for men aged 60 years and to 5.50% for men aged 70 years [6]. In 2014, the highest incidence rates for PCa in the US were in the age group of 65-74 years, while between 1975-1995 the incidence rates were in the group of 75 years or older indicating that the diagnosis is currently made at younger age [7]. The incidence rates for PCa are highly variable between different geographical areas, with highest incidence in industrialized countries [6]. Since autopsy-based detection of PCa revealed similar prevalence rates among different geographical areas, the increasing incidence is significantly associated with the widespread implementation of PSA testing leading to elevated biopsy-based detection rates in asymptomatic patients [8, 9]. The mortality pattern has largely remained unchanged and shows less variation worldwide, as PSA testing has a greater impact on incidence than on mortality [6, 8]. Family history is an important contributing factor for the incidence of PCa (men with affected
Load more

Recommended publications
  • Entrez Symbols Name Termid Termdesc 117553 Uba3,Ube1c
    Entrez Symbols Name TermID TermDesc 117553 Uba3,Ube1c ubiquitin-like modifier activating enzyme 3 GO:0016881 acid-amino acid ligase activity 299002 G2e3,RGD1310263 G2/M-phase specific E3 ubiquitin ligase GO:0016881 acid-amino acid ligase activity 303614 RGD1310067,Smurf2 SMAD specific E3 ubiquitin protein ligase 2 GO:0016881 acid-amino acid ligase activity 308669 Herc2 hect domain and RLD 2 GO:0016881 acid-amino acid ligase activity 309331 Uhrf2 ubiquitin-like with PHD and ring finger domains 2 GO:0016881 acid-amino acid ligase activity 316395 Hecw2 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 GO:0016881 acid-amino acid ligase activity 361866 Hace1 HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 GO:0016881 acid-amino acid ligase activity 117029 Ccr5,Ckr5,Cmkbr5 chemokine (C-C motif) receptor 5 GO:0003779 actin binding 117538 Waspip,Wip,Wipf1 WAS/WASL interacting protein family, member 1 GO:0003779 actin binding 117557 TM30nm,Tpm3,Tpm5 tropomyosin 3, gamma GO:0003779 actin binding 24779 MGC93554,Slc4a1 solute carrier family 4 (anion exchanger), member 1 GO:0003779 actin binding 24851 Alpha-tm,Tma2,Tmsa,Tpm1 tropomyosin 1, alpha GO:0003779 actin binding 25132 Myo5b,Myr6 myosin Vb GO:0003779 actin binding 25152 Map1a,Mtap1a microtubule-associated protein 1A GO:0003779 actin binding 25230 Add3 adducin 3 (gamma) GO:0003779 actin binding 25386 AQP-2,Aqp2,MGC156502,aquaporin-2aquaporin 2 (collecting duct) GO:0003779 actin binding 25484 MYR5,Myo1e,Myr3 myosin IE GO:0003779 actin binding 25576 14-3-3e1,MGC93547,Ywhah
    [Show full text]
  • Potential Role Vasculogenesis in Lupus Are Mediated
    Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 Kaplan is online at: on α average * The Journal of Immunology published online 30 August 2010 from submission to initial decision 4 weeks from acceptance to publication The Detrimental Effects of IFN- http://www.jimmunol.org/content/early/2010/08/30/jimmun ol.1001782 Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction J Immunol Seth G. Thacker, Celine C. Berthier, Deborah Mattinzoli, Maria Pia Rastaldi, Matthias Kretzler and Mariana J. Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2010/08/30/jimmunol.100178 2.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 28, 2021. Published August 30, 2010, doi:10.4049/jimmunol.1001782 The Journal of Immunology The Detrimental Effects of IFN-a on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction Seth G. Thacker,*,1 Celine C. Berthier,†,1 Deborah Mattinzoli,‡ Maria Pia Rastaldi,‡ Matthias Kretzler,† and Mariana J.
    [Show full text]
  • The DNA Sequence and Comparative Analysis of Human Chromosome 20
    articles The DNA sequence and comparative analysis of human chromosome 20 P. Deloukas, L. H. Matthews, J. Ashurst, J. Burton, J. G. R. Gilbert, M. Jones, G. Stavrides, J. P. Almeida, A. K. Babbage, C. L. Bagguley, J. Bailey, K. F. Barlow, K. N. Bates, L. M. Beard, D. M. Beare, O. P. Beasley, C. P. Bird, S. E. Blakey, A. M. Bridgeman, A. J. Brown, D. Buck, W. Burrill, A. P. Butler, C. Carder, N. P. Carter, J. C. Chapman, M. Clamp, G. Clark, L. N. Clark, S. Y. Clark, C. M. Clee, S. Clegg, V. E. Cobley, R. E. Collier, R. Connor, N. R. Corby, A. Coulson, G. J. Coville, R. Deadman, P. Dhami, M. Dunn, A. G. Ellington, J. A. Frankland, A. Fraser, L. French, P. Garner, D. V. Grafham, C. Grif®ths, M. N. D. Grif®ths, R. Gwilliam, R. E. Hall, S. Hammond, J. L. Harley, P. D. Heath, S. Ho, J. L. Holden, P. J. Howden, E. Huckle, A. R. Hunt, S. E. Hunt, K. Jekosch, C. M. Johnson, D. Johnson, M. P. Kay, A. M. Kimberley, A. King, A. Knights, G. K. Laird, S. Lawlor, M. H. Lehvaslaiho, M. Leversha, C. Lloyd, D. M. Lloyd, J. D. Lovell, V. L. Marsh, S. L. Martin, L. J. McConnachie, K. McLay, A. A. McMurray, S. Milne, D. Mistry, M. J. F. Moore, J. C. Mullikin, T. Nickerson, K. Oliver, A. Parker, R. Patel, T. A. V. Pearce, A. I. Peck, B. J. C. T. Phillimore, S. R. Prathalingam, R. W. Plumb, H. Ramsay, C. M.
    [Show full text]
  • Enzymatische Alkinfunktionalisierung Zur Markierung Und Identifizierung
    Enzymatische Alkinfunktionalisierung zur Markierung und Identifizierung von Protein-Methyltransferase-Substraten Von der Fakultat¨ f¨ur Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der Naturwissenschaften genehmigte Dissertation vorgelegt von Diplom-Gymnasiallehrerin Sophie Willnow aus Hattingen Berichter: Universitatsprofessor¨ Dr. Elmar Weinhold Universitatsprofessor¨ Dr. Bernhard L¨uscher Tag der m¨undlichen Pr¨ufung: 06. Juli 2012 Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verf¨ugbar. Diese Arbeit wurde im Zeitraum von September 2008 bis Oktober 2011 am Institut f¨ur Orga- nische Chemie der Rheinisch-Westf¨alischen Technischen Hochschule Aachen (RWTH Aachen University) unter Anleitung von Prof. Dr. Elmar Weinhold und am Institut f¨ur Biochemie und Molekularbiologie des Universit¨atsklinikums Aachen unter Anleitung von Prof. Dr. Bernhard L¨uscher angefertigt. Mein Dank gilt an erster Stelle Prof. Dr. Elmar Weinhold f¨ur die interessante interdisziplin¨are Themenstellung zwischen Chemie und Biologie, f¨ur das entgegengebrachte Vertrauen, auch eigene Ideen umsetzen zu k¨onnen, und f¨ur die vielen konstruktiven Diskussionen. Ich bedanke mich außerdem herzlich bei Prof. Dr. Bernhard L¨uscher f¨ur die vielen hilfreichen Anmerkungen und Einsch¨atzungen. Teile dieser Arbeit wurden bereits ver¨offentlicht: 1. W. Peters, S. Willnow, M. Duisgen, H. Kleine, T. Macherey, K. E. Duncan, D. W. Litch- field, B. L¨uscher, E. Weinhold. Enzymatic Site-Specific Functionalization of Protein Me- thyltransferase Substrates with Alkynes for Click Labeling. Angew. Chem. 2010, 122, 5296–5299; Angew. Chem. Int. Ed. 2010, 49, 5170–5173. 2. Y. Motorin, J. Burhenne, R. Teimer, K. Koynov, S. Willnow, E. Weinhold, M.
    [Show full text]
  • REPORT CHMP4B, a Novel Gene for Autosomal Dominant Cataracts Linked to Chromosome 20Q
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT CHMP4B, a Novel Gene for Autosomal Dominant Cataracts Linked to Chromosome 20q Alan Shiels, Thomas M. Bennett, Harry L. S. Knopf, Koki Yamada, Koh-ichiro Yoshiura, Norio Niikawa, Soomin Shim, and Phyllis I. Hanson Cataracts are a clinically diverse and genetically heterogeneous disorder of the crystalline lens and a leading cause of visual impairment. Here we report linkage of autosomal dominant “progressive childhood posterior subcapsular” cataracts segregating in a white family to short tandem repeat (STR) markers D20S847 (LOD score [Z] 5.50 at recombination fraction [v] 0.0) and D20S195 (Z p 3.65 atv p 0.0 ) on 20q, and identify a refined disease interval (rs2057262–(3.8 Mb)–rs1291139) by use of single-nucleotide polymorphism (SNP) markers. Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.386ArT) in exon 3 of the gene for chromatin modifying protein-4B (CHMP4B)thatwas predicted to result in the nonconservative substitution of a valine residue for a phylogenetically conserved aspartic acid residue at codon 129 (p.D129V). In addition, we have detected a heterozygous transition (c.481GrA) in exon 3 of CHMP4B cosegregating with autosomal dominant posterior polar cataracts in a Japanese family that was predicted to result in the missense substitution of lysine for a conserved glutamic acid residue at codon 161 (p.E161K). Transfection studies of cultured cells revealed that a truncated form of recombinant D129V-CHMP4B had a different subcellular distribution than wild type and an increased capacity to inhibit release of virus-like particles from the cell surface, consistent with deleterious gain-of-function effects.
    [Show full text]
  • Hedayatollah Hosseini
    Molecular mechanism of early metastatic breast cancer dissemination Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Biologie und Vorklinische Medizin der Universität Regensburg vorgelegt von Hedayatollah Hosseini aus Ahwaz, Iran 2016 Das Promotionsgesuch wurde eingereicht am 14.Dec. 2016 Die Arbeit wurde angeleitet von Herr Prof. Dr. Christoph A. Klein Untershrift: 2 Contents 1 Introduction ........................................................................................................................................................ 7 1.1 Metastasis ..................................................................................................................................................... 7 1.2 Local invasion and migration ....................................................................................................................... 8 1.3 Cancer stem cells in metastasis ..................................................................................................................... 9 1.4 Mammary gland development and breast cancer ........................................................................................ 10 1.5 Early versus late dissemination of cancer cells........................................................................................... 14 1.6 Balb-NeuT as a mouse model for early dissemination ............................................................................... 15 1.7 Aim of work ..............................................................................................................................................
    [Show full text]
  • Table S5-Correlation of Cytogenetic Changes with Gene Expression
    Table S5-Correlation of cytogenetic changes with gene expression in MCF10CA1a FeatureNumCytoband GeneName Description logFC Fold change 28 4087 2p21 TACSTD1 Homo sapiens tumor-associated calcium signal transducer 1 (TACSTD1), mRNA-7.04966 [NM_002354]0.007548158 37 38952 20p12.2 JAG1 Homo sapiens jagged 1 (Alagille syndrome) (JAG1), mRNA [NM_000214] -6.44293 0.011494322 67 2569 20q13.33 COL9A3 Homo sapiens collagen, type IX, alpha 3 (COL9A3), mRNA [NM_001853] -6.04499 0.015145263 72 44151 2p23.3 KRTCAP3 Homo sapiens clone DNA129535 MRV222 (UNQ3066) mRNA, complete cds. [AY358993]-6.03013 0.015302019 105 40016 8q12.1 CA8 Homo sapiens carbonic anhydrase VIII (CA8), mRNA [NM_004056] 5.68101 51.30442111 129 34872 20q13.32 SYCP2 Homo sapiens synaptonemal complex protein 2 (SYCP2), mRNA [NM_014258]-5.21222 0.026975242 140 27988 2p11.2 THC2314643 Unknown -4.99538 0.031350145 149 12276 2p23.3 KRTCAP3 Homo sapiens keratinocyte associated protein 3 (KRTCAP3), mRNA [NM_173853]-4.97604 0.031773429 154 24734 2p11.2 THC2343678 Q6E5T4 (Q6E5T4) Claudin 2, partial (5%) [THC2343678] 5.08397 33.91774866 170 24047 20q13.33 TNFRSF6B Homo sapiens tumor necrosis factor receptor superfamily, member 6b, decoy (TNFRSF6B),-5.09816 0.029194423 transcript variant M68C, mRNA [NM_032945] 177 39605 8p11.21 PLAT Homo sapiens plasminogen activator, tissue (PLAT), transcript variant 1, mRNA-4.88156 [NM_000930]0.033923737 186 31003 20p11.23 OVOL2 Homo sapiens ovo-like 2 (Drosophila) (OVOL2), mRNA [NM_021220] -4.69868 0.038508469 200 39605 8p11.21 PLAT Homo sapiens plasminogen activator, tissue (PLAT), transcript variant 1, mRNA-4.78576 [NM_000930]0.036252773 209 9317 2p14 ARHGAP25 Homo sapiens Rho GTPase activating protein 25 (ARHGAP25), transcript variant-4.62265 1, mRNA0.040592167 [NM_001007231] 211 39605 8p11.21 PLAT Homo sapiens plasminogen activator, tissue (PLAT), transcript variant 1, mRNA -4.7152[NM_000930]0.038070134 212 16979 2p13.1 MGC10955 Homo sapiens hypothetical protein MGC10955, mRNA (cDNA clone MGC:10955-4.70762 IMAGE:3632495),0.038270716 complete cds.
    [Show full text]
  • Long Pre-Mrna Depletion and RNA Missplicing Contribute to Neuronal Vulnerability from Loss of TDP-43
    ARTICLES Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43 Magdalini Polymenidou1,2,6, Clotilde Lagier-Tourenne1,2,6, Kasey R Hutt2,3,6, Stephanie C Huelga2,3, Jacqueline Moran1,2, Tiffany Y Liang2,3, Shuo-Chien Ling1,2, Eveline Sun1,2, Edward Wancewicz4, Curt Mazur4, Holly Kordasiewicz1,2, Yalda Sedaghat4, John Paul Donohue5, Lily Shiue5, C Frank Bennett4, Gene W Yeo2,3 & Don W Cleveland1,2 We used cross-linking and immunoprecipitation coupled with high-throughput sequencing to identify binding sites in 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease–associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3′ untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation. Amyotrophic lateral sclerosis (ALS) is an adult-onset disorder in which RNA processing regulation in neuronal integrity. However, a compre- premature loss of motor neurons leads to fatal paralysis. Most cases hensive protein-RNA interaction map for TDP-43 and identification of ALS are sporadic, with only 10% of affected individuals having a of post-transcriptional events that may be crucial for neuronal survival familial history.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,067,168 B2 Ordway Et Al
    USOO80671 68B2 (12) United States Patent (10) Patent No.: US 8,067,168 B2 Ordway et al. (45) Date of Patent: Nov. 29, 2011 (54) GENE METHYLATION IN CANCER OTHER PUBLICATIONS DAGNOSIS GenBank Locus AF369786 Homo sapiens growth hormone Secretagogue receptor gene, complete cols, alternatively spliced (Jul. (75) Inventors: Jared Ordway, St. Louis, MO (US); 7, 2001), from www.ncbi.nlm.nih.gov. 5 printed pages.* Jeffrey A. Jeddeloh, Oakville, MO Juppner H. Bone (1995) vol. 17 No. 2 Supplement, pp. 39S-42S.* (US); Joseph Bedell, Chesterfield, MO GenBank Locus AC069523 “Homo sapiens 3 BAC RP11-1K20 (Roswell Park Cancer Institute Human BAC Library) complete (US) sequence” (Aug. 30, 2002) from www.ncbi.nlm.nih.gov, pp. 1-31.* Rein T. et al. Nucleic Acids Research (1998) vol. 26, No. 10, pp. (73) Assignee: Orion Genomics LLC, St. Louis,MO 2255-2264. (US) Gaytan F. etal. The Journal of Clinical Endocrinology & Metabolism (Mar. 2005) vol. 90, No. 3, pp. 1798-1804.* (*) Notice: Subject to any disclaimer, the term of this Cmaeron E.E. et al Blood (Oct. 1, 1999) vol. 94, No. 7, p. 2445 patent is extended or adjusted under 35 2451.* Costello, Josoph F. et al.; “Graded Methylation in the Promoter and U.S.C. 154(b) by 462 days. BOdy of the O-Methylguanine DNA Methyltransferase (MGMT) Gene Correlates with MGMT Expression in Human Glioma Cells'; (21) Appl. No.: 11/809,355 1994. The Journal of Biological Chemistry, vol. 269, No. 25, pp. 17228-17237. (22) Filed: May 30, 2007 Widschwendter, Martin et al.; "Methylation and Silencing of the Retinoic Acid Receptor-B2 Gene in Breast Cancer'; 2000, Journal of (65) Prior Publication Data the National Cancer Institute, vol.
    [Show full text]
  • Analyse Des Transcriptomes Du Cerveau De Souris
    Analyse des transcriptomes du cerveau de souris : mise en évidence de patrons régionaux d’expression conservés chez l’homme et altérés dans des modèles de maladies neurodégénératives Camille Brochier To cite this version: Camille Brochier. Analyse des transcriptomes du cerveau de souris : mise en évidence de patrons ré- gionaux d’expression conservés chez l’homme et altérés dans des modèles de maladies neurodégénéra- tives. Sciences du Vivant [q-bio]. Université Paris Sud - Paris XI, 2007. Français. tel-00361207 HAL Id: tel-00361207 https://tel.archives-ouvertes.fr/tel-00361207 Submitted on 13 Feb 2009 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. UNIVERSITE PARIS SUDSUD----XIXIXIXI FACULTE DES SCIENCES D’ORSAY Année 2007 THESE pour obtenir le grade de DOCTEUR DE L’UNIVERSITE PARIS XI SPECIALITE : GENOMIQUE ECOLE DOCTORALE : « GENES, GENOMES, CELLULES » presentée et soutenue publiquement par Camille BBROCHIERROCHIER Le 21 Septembre 2007 Analyse des transcriptomes du cerveau de souris : Mise en évidence de patrons régionaux d’expression conservés chez l’homme et altérés dans des modèles de maladies neurodégénératives JURY Mme Monique BOLOTINBOLOTIN----FUKUHARAFUKUHARA Présidente Mme Brigitte KIEFFER Rapporteuse MMM.M. Gilbert VASSART Rapporteur Melle Tania VITALIS Examinatrice MMM.M.
    [Show full text]
  • Supplementary Table S5
    Supplementary Table S5 - Genes upregulated by anti-MYCN PNA ProbeID Symbol Description RH30ctrl_SignalRH30mut__SignalRH30pna_Signalpna vs mut pna vs ctrl 206884_s_at SCEL sciellin 2.4 3.3 51.4 3.961 4.421 208266_at C8orf17 chromosome 8 open reading frame 17 16.9 4.1 52.1 3.668 1.624 217462_at C11orf9 chromosome 11 open reading frame 9 2.9 10.9 108.9 3.321 5.231 202175_at CHPF 215 123.9 939 2.922 2.127 210271_at NEUROD2 neurogenic differentiation 2 2.4 13.1 84.6 2.691 5.140 216058_s_at CYP2C19 cytochrome P450, family 2, subfamily C, polypeptide 19 4.8 12.8 78.2 2.611 4.026 205556_at MSX2 msh homeobox homolog 2 (Drosophila) 18.7 9 52.6 2.547 1.492 217500_at TIAL1 TIA1 cytotoxic granule-associated RNA binding protein-like 1 15.3 16.2 91.3 2.495 2.577 217124_at IQCE IQ motif containing E 25.8 22.3 116.7 2.388 2.177 213929_at 8.3 14 66.5 2.248 3.002 221159_at 33.4 19.1 81.5 2.093 1.287 207498_s_at CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6 60.8 28.7 110.9 1.950 0.867 210881_s_at IGF2 insulin-like growth factor 2 (somatomedin A) 1556.7 1187.4 4274.8 1.848 1.457 219315_s_at C16orf30 chromosome 16 open reading frame 30 83 61.2 213 1.799 1.360 202410_x_at IGF2 insulin-like growth factor 2 (somatomedin A) 2587.4 1916.7 6376.5 1.734 1.301 220748_s_at ZNF580 zinc finger protein 580 298.5 218.7 722.9 1.725 1.276 221063_x_at RNF123 ring finger protein 123 148.5 84.9 277.3 1.708 0.901 210280_at MPZ myelin protein zero (Charcot-Marie-Tooth neuropathy 1B) 48.7 49.5 160.5 1.697 1.721 205236_x_at SOD3 superoxide dismutase 3, extracellular
    [Show full text]
  • Gene Expression for HIV-Associated Dementia and HIV Encephalitis in Microdissected Neurons 1: Preliminary Analysis
    Neurobehavioral HIV Medicine Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Gene expression for HIV-associated dementia and HIV encephalitis in microdissected neurons 1: preliminary analysis Paul Shapshak1,2 Abstract: We analyzed gene expression in neurons from 16 cases divided into four groups, ie, Robert Duncan3 human immunodeficiency virus (HIV)-associated dementia (HAD)/HIV encephalitis (HAD/ E Margarita Duran4 HIVE), HAD alone, HIVE alone, and HIV positive alone. We produced the neurons using laser Fabiana Farinetti5 capture microdissection from cryopreserved basal ganglia (specifically globus pallidus). Gene Alireza Minagar6 expression in pooled neurons from each case was analyzed on GE CodeLink Microarray chips Deborah Commins7,8 with 55,000 gene fragments per chip. One-way analysis of variance showed significant changes in expression of 197 genes among the four groups (P , 0.005). The three groups, ie, HAD/HIVE, Hector Rodriguez9 HAD alone, and HIVE alone, were compared with the HIV-positive group using Fisher’s least Francesco Chiappelli10 significant difference test, and associated gene expression changes were assigned to each of the Pandajarasamme For personal use only. three comparisons. Identified genes were associated with 159 functional categories and many 11,12 Kangueane of the genes had more than one function. The functional groups included adhesion, amyloid, 8,13 Andrew J Levine apoptosis, channel complex, cell cycle, chaperone, chromatin, cytokine, cytoskeleton, metabolism, Elyse Singer8,13 mitochondria, multinetwork detection protein, sensory perception, receptor, ribosome, noncoding Charurut Somboonwit1,14 miRNA, signaling, synapse, transcription factor, homeobox, transport, multidrug resistance, and John T Sinnott1,14 ubiquitin cycle. Several genes were associated with other neurodegenerative and developmental 1Division of Infectious Disease and International diseases, including Alzheimer’s disease, Huntington’s disease, and diGeorge syndrome.
    [Show full text]