DOCSLIB.ORG

Martina Anna Finetti

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Martina Anna Finetti Next-Generation Sequencing Identifies Mechanisms Of Tumourigenesis Caused By Loss Of SMARCB1 In Malignant Rhabdoid Tumours Martina Anna Finetti Thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy Newcastle University Faculty of Medical Sciences Northern Institute for Cancer Research December 2014 Declaration I certify that no part of the material documented in this thesis has previously been submitted for a degree or other qualification in this or any other university. I declare that this thesis represents my own unaided work, carried out by myself, except where it is acknowledged otherwise in the thesis text. Martina Finetti December 2014 I Acknowledgements I would like to express my sincere gratitude to my supervisors, Dr. Daniel Williamson, Professor Steven Clifford, and Professor Simon Bailey. Their continuous support and their extraordinary knowledge of paediatric cancer and bioinformatics have helped me immensely throughout my research. I would also like to thank my assessors Professor John Lunec and Dr. Luke Gaughan and Professor Craig Robson for their constant guidance and encouragement for the last four years. I would like to thank the members of the Paediatric Brain Tumour Research Group. In particular I would like to thank Dr. Rebecca Hill, Matthew Selby and Dr Dolores Hamilton for the support, the encouragement and the time spent together in good and bad times. Special thanks go to all people at Sir James Spence Institute for their technical help and support. I would in particular thank Stefano and Alicia for our friendship: thank you for the moral support and the all the laughs we shared in between experiments! I would like to thank the NECCR, Children with cancer UK, Brain Trust, Love Oliver, CCLG, Karen and Iain Wark, The Smiley Ridley Fund, whose financial support made this project possible. Finally, I would like to thank my family: my Mum Chiara, Lorenzo, Giulia and Al. Thank you for supporting me especially in the bad times and for all your caring: without your encouragement I would not have made it. My final thanks are reserved for my Dad Roberto: your love for knowledge inspires me to continue my studies and accomplish my dreams. II Dedication This thesis is dedicated to the memory of my Dad, Roberto Finetti. How I wish, how I wish you were here. We're just two lost souls swimming in a fish bowl, year after year, Running over the same old ground. What have we found? The same old fears. Wish you were here -Pink Floyd- III Abstract Introduction: Malignant Rhabdoid Tumours (MRT) are unique malignancies caused by biallelic inactivation of a single gene (SMARCB1). SMARCB1 encodes for a protein that is part of the SWI/SNF chromatin remodelling complex, responsible for the regulation of hundreds of downstream genes/pathways. Despite the simple biology of these tumours, no studies have identified the critical pathways involved in tumourigenesis. The understanding of downstream effects is essential to identifying therapeutic targets that can improve the outcome of MRT patients. Methods: RNA-seq and 450K-methylation analyses have been performed in MRT human primary malignancies (n > 39) and in 4 MRT cell lines in which lentivirus was used to re-express SMARCB1 (G401, A204, CHLA-266, and STA-WT1). The MRT cell lines were treated with 5-aza-2 -deoxycytidine followed by global gene transcription analysis (RNA-seq and 450K-methylation) to investigate how changes in methylation lead to tumourigenesis. Results: We show that primary Malignant Rhabdoid Tumours present a unique and distinct expression/methylation profile which confirms that MRT broadly constitute a single and different tumour type from other paediatric malignancies. However, despite their common cause MRT can be can sub-group by location (i.e. CNS or kidney). We observe that re-expression of SMARCB1 in MRT cell lines determines activation/inactivation of specific downstream pathways such as IL-6/TGF beta. We also observe a direct correlation between alterations in methylation and gene expression in CD44, GLI2, GLI3, CDKN1A, CDKN2A and JARID after SMARB1 re-expression. Loss of SMARCB1 also promotes expression of aberrant isoforms and novel transcripts and causes genome-wide changes in SWI/SNF binding. Conclusion: Next generation transcriptome and methylome analysis in primary MRT and in functional models give us detailed downstream effects of SMARCB1 loss in Malignant Rhabdoid Tumours. The integration of data from both primary and functional models has provided, for the first time, a genome-wide catalogue of SMARCB1 tumourigenic changes (validated using systems biology). Here we show how a single IV deletion of SMARCB1 is responsible for deregulation of expression, methylation status and binding at the promoter regions of potent tumour-suppressor genes. The genes, pathways and biological mechanisms indicated as key in tumour development may ultimately be targetable therapeutically and will lead to better treatments for what is currently one of the most lethal paediatric cancers. V List of abbreviation H2A Histone 2A µg Microgram µl Microliter 3’ UTR Three Prime Untranslated Region 5-azaCdR 5-Aza-2’-Deoxycytidine A Adenine AATK Apoptosis-Associated Tyrosine Kinase Ab Antibody ABR Active BCR-Related AKT V-Akt Murine Thymoma Viral Oncogene AML Acute Myelogenous Leukaemia APC Adenomatous Polyposis Coli ARID1A/ BAF250a AT Rich Interactive Domain 1A (SWI-Like) VI ATPase Adenylpyrophosphatase ATRT Atypical Teratoid Rhabdoid Tumours AZA 5-Aza-2-Deoxycytidine B2M Beta-2-Microglobulin BAF155 BRG1-Associated Factor 155 BAF170 BRG1-Associated Factor 170 BASH Beadarray Subversion Of Harshlight BCA Bicinchoninic Acid Assay BCL2 B-Cell CLL / Lymphoma 2 B-FABP Brain Fatty Acid-Binding Protein BHLHE40 Basic Helix-Loop-Helix Family, Member E40 BID BH3 Domain-Containing Proapoptotic Bcl2 Family Member BK PDZ-Binding Kinase BLAST Basic Local Alignment Search Tool VII BM1 Polycomb Complex Protein BMI1 BMI Polycomb Ring Finger Oncogene BP Base Pair BRAF V-Raf Murine Sarcoma Viral Oncogene Homologue B1 BRCA1/2 Breast Cancer 1/2 BRG1 Brahma-Related Gene 1 BRM Brahma BTG4 B-Cell Translocation Gene 4 C Cytosines C2 Curated Gene Sets C6 Oncogenic Signatures CASP8 Caspase 8, Apoptosis-Related Cysteine Peptidase CCDC46 Coiled-Coil Domain Containing 46 CCDC74B Coiled-Coil Domain Containing 74B CCLG Children's Cancer And Leukaemia Group VIII CCNB1 Cyclin B1 CD8 (Cluster Of Differentiation 8 CDH1 Cadherin 1, Type 1, E-Cadherin (Epithelial) CDKN1A Cyclin Dependent Kinase Inhibitor 1A CDKN2A Cyclin-Dependent Kinase Inhibitor 2A cDNA Complementary DNA CDS Similarly Coding Sequences CHD5 Chromo domain Helicase DNA Binding Protein 5 ChIP Chromatin Immunoprecipitation ChIP-seq Chromatin Immunoprecipitation Sequencing CLAS Classic Type Medulloblastoma CML Chronic Myelogenous Leukaemia CNAs Copy-Number Aberrations CNN Copy Number Neutral CNS Central Nervous System IX COL1A2 Collagen, Type I, Alpha 2 Conc Concentration CpG Cytosine-Guanine Dinucleotide cRNA Complementary RNA CTCF CCCTC-Binding Factor (Zinc Finger Protein) CTL Control CTTNB1 Catenin (Cadherin-Associated Protein), Beta 1 Cy3 Cyanine 3 Dye Cy5 Cyanine 5 Dye DAVID Discovery Database For Annotation, Visualization And Integrated DAZ Deleted In Azoospermia DCLK1 Doublecortin-Like Kinase 1 DHH Desert Hedgehog DLC1 Deleted In Liver Cancer 1 DMSO Dimethyl Sulfoxide X DN Dominant Negative DN Desmoplastic / Nodular Medulloblastoma DNA Deoxyribose Nucleic Acid DNA2 DNA Replication Helicase/Nuclease 2 DNM3OS NM3 Opposite Strand/Antisense RNA DNMT1 DNA Methyltransferase 1 DNMT3A DNA Methyltransferase 3A DNMT3B DNA Methyltransferase 3B dNTPs Nucleoside Triphosphates Containing Deoxyribose DRAXIN Dorsal Inhibitory Axon Guidance Protein E. coli Escherichia Coli E2F1 E2F Transcription Factor 1 E2F3 E2F Transcription Factor 3 E2F4 E2F Transcription Factor 4 ECRT Extra Cranial Rhabdoid Tumours XI EGFR Epidermal Growth Factor Receptor EGL External Granule Layer EPCAM Epithelial Cell Adhesion Molecule ER- Estrogen-Receptor Negative ERBB2 V-Erb-B2 Erythroblastic Leukaemia Viral Oncogene Homologue2,Neuroma / Glioblastoma ES Embryonic Stem ES Enrichment Score EU-RHAB European Rhabdoid Registry EWAS Epigenome-Wide Association Studies EWS Ewing Sarcoma Breakpoint Region 1 EZH2 Enhancer Of Zeste Homolog 2 FBXW8 F-Box And WD Repeat Domain Containing 8, FDR False Discovery Rate FPKM Fragments Per Kilo-Base Of Exon Per Million Fragments Mapped) XII FPKM Fragments Per Kilobases Per Millon Reads Fwd Forward G Guanine GA Genome Analyser Gal-1 Galactokinasi 1 GALNT2 Polypeptide N-Acetylgalactosaminyltransferase 2 GAPDH Glyceraldehyde-3-Phosphate Dehydrogenase GC% Guanine-Cytosine Content GCS Genome Analyser Control Software gDNA Genomic DNA GEO Gene Expression Omnibus GFAP Glial Fibrillary Acidic Protein GLI1 GLI Family Zinc Finger 1 GLI2 GLI Family Zinc Finger 2 GLI2 GLI Family Zinc Finger 2 XIII GLI3 GLI Family Zinc Finger 3 GLI3 GLI Family Zinc Finger 3 GPx-1 Glutathione Peroxidase 1 GPx-2 Glutathione Peroxidase 2 GSEA Gene Set Enrichment Analysis GTP Guanine Triphosphate Gy Gray (Unit) g G-Force H2.AZ Variant Histone 2 Az H2B Histone 2B H2O Dihydrogen Monoxide H3 Histone 3 H3K27me3 Histone 3 Lysine 27 Trimethylation H3K36me3 Histone 3 Lysine 36 Trimethylation H3K4me3 Histone 3 Lysine 4 Trimethylation XIV H4 Histone 4 HATs Histone Acetyltransferases HC Hierarchical Clustering HC Hierarchical Clustering HDAC1 Histone Deacetylase 1 HDAC2 Histone Deacetylase 2 HDACs Histone Deacetylase HDCT High-Dose-Chemotherapy
Load more

Recommended publications
  • Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected]
    University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School July 2017 Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Pathology Commons Scholar Commons Citation Mohamed, Mai, "Role of Amylase in Ovarian Cancer" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6907 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Role of Amylase in Ovarian Cancer by Mai Mohamed A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Pathology and Cell Biology Morsani College of Medicine University of South Florida Major Professor: Patricia Kruk, Ph.D. Paula C. Bickford, Ph.D. Meera Nanjundan, Ph.D. Marzenna Wiranowska, Ph.D. Lauri Wright, Ph.D. Date of Approval: June 29, 2017 Keywords: ovarian cancer, amylase, computational analyses, glycocalyx, cellular invasion Copyright © 2017, Mai Mohamed Dedication This dissertation is dedicated to my parents, Ahmed and Fatma, who have always stressed the importance of education, and, throughout my education, have been my strongest source of encouragement and support. They always believed in me and I am eternally grateful to them. I would also like to thank my brothers, Mohamed and Hussien, and my sister, Mariam. I would also like to thank my husband, Ahmed.
    [Show full text]
  • Bioinformatic Analysis of Autism Positional Candidate Genes Using Biological Databases and Computational Gene Network Prediction
    Genes, Brain and Behavior (2003) 2: 303–320 Copyright # Blackwell Munksgaard 2003 Bioinformatic analysis of autism positional candidate genes using biological databases and computational gene network prediction A. L. Yonan†,‡, A. A. Palmer†, K. C. Smith†, inform studies of autism, and to illustrate and explore I. Feldman†,††, H. K. Lee†, J. M. Yonan§, the increasing potential of bioinformatic approaches as † †,†† *,†,‡, S. G. Fischer , P. Pavlidis and T. C. Gilliam { a compliment to linkage analysis. Keywords: 17q, AGRE sample, autism, association studies, †Columbia Genome Center, Columbia University, New York, bioinformatics, candidate genes ‡ Department of Genetics and Development, Columbia University, Received 30 June 2003, revised 20 August 2003, accepted New York, for publication 21 August 2003 ¶Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, §Division of Molecular Genetics, Departments of Pediatrics and Medicine, Columbia University, New York, Autism is a pervasive neurodevelopmental disorder that ††Department of Biomedical Informatics, Columbia University, severely impairs development of normal social and emotional New York, USA interactions and related forms of communication. Disease *Corresponding author: T. C. Gilliam, Columbia Genome Center, symptoms characteristically include unusually restricted and 1150 St. Nicholas Avenue, Room 508, New York, NY 10032, USA. E-mail: [email protected] stereotyped patterns of behaviors and interests. Autism describes the most severe manifestation
    [Show full text]
  • Effect of Occupational Exposures on Lung Cancer Susceptibility: a Study of Gene-Environment Interaction Analysis
    Author Manuscript Published OnlineFirst on January 12, 2015; DOI: 10.1158/1055-9965.EPI-14-1143-T Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Effect of Occupational Exposures on Lung Cancer Susceptibility: A Study of Gene-Environment Interaction Analysis Jyoti Malhotra1, Samantha Sartori1, Paul Brennan2, David Zaridze3, Neonila Szeszenia- Dabrowska4, Beata Świątkowska4, Peter Rudnai5, Jolanta Lissowska6, Eleonora Fabianova7, Dana Mates8, Vladimir Bencko9, Valerie Gaborieau2, Isabelle Stücker10, Lenka Foretova11, Vladimir Janout12, Paolo Boffetta1 1Icahn School of Medicine at Mount Sinai, New York, USA 2International Agency for Research on Cancer, Lyon, France 3Russian Cancer Research Center, Moscow, Russia 4Department of Epidemiology, The Nofer Institute of Occupational Medicine, Lodz, Poland 5National Institute of Environmental Health, Budapest, Hungary 6M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 7Department of Occupational Health, Specialized State Health Institute, Banska Bystrica, Slovakia 8National Institute of Public Health, Bucharest, Romania 9Institute of Hygiene and Epidemiology, Charles University, First Faculty of Medicine, Prague, Czech Republic 10Centre for Research in Epidemiology and Population Health, INSERM, France 11Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU Brno, Czech Republic 12Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic Running title: Gene-occupation interactions in Lung cancer risk Key words: Lung cancer, GWAS, Gene-environment interaction, Occupational exposures Financial support: Subject recruitment for INCO-Copernicus study was supported by a grant from the European Commission’s INCO-COPERNICUS program (Contract No IC15-CT96- 0313). This project was also partially supported by a grant of the French National Cancer Institute (InCA) to P.
    [Show full text]
  • Highly Aneuploid Zebrafish Malignant Peripheral Nerve Sheath Tumors
    Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers GuangJun Zhanga, Sebastian Hoerscha,b, Adam Amsterdama, Charles A. Whittakera, Jacqueline A. Leesa, and Nancy Hopkinsa,1 aDepartment of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and bBioinformatics Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Contributed by Nancy Hopkins, August 17, 2010 (sent for review June 30, 2010) Aneuploidy is a hallmark of human cancers, but most mouse cancer do not display the extensive aneuploidy seen in many types of models lack the extensive aneuploidy seen in many human tumors. human tumors. For this reason, researchers have engineered The zebrafish is becoming an increasingly popular model for studying mouse cancer models with chromosomal instability. Such mice cancer. Here we report that malignant peripheral nerve sheath tumors develop tumors that are highly aneuploid and also possess sub- (MPNSTs) that arise in zebrafish as a result of mutations in either chromosomal alterations. These alterations can then be exploited ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyp- to identify genetic alterations that drive the cancer phenotype (12). ing reveals that these tumors frequently harbor near-triploid numbers Comparison of T-cell acute lymphoblastic leukemia (T-ALL) in of chromosomes, and they vary in chromosome number from cell to this mouse model with human T-ALL using array CGH (aCGH) cell within a single tumor. Using array comparative genomic hybrid- indicated important roles of FBXW7 and PTEN in this tumor type ization, we found that, as in human cancers, certain fish chromosomes (12).
    [Show full text]
  • Downloaded from Ensembl
    UCSF UC San Francisco Electronic Theses and Dissertations Title Detecting genetic similarity between complex human traits by exploring their common molecular mechanism Permalink https://escholarship.org/uc/item/1k40s443 Author Gu, Jialiang Publication Date 2019 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California by Submitted in partial satisfaction of the requirements for degree of in in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, SAN FRANCISCO AND UNIVERSITY OF CALIFORNIA, BERKELEY Approved: ______________________________________________________________________________ Chair ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________ Committee Members ii Acknowledgement This project would not have been possible without Prof. Dr. Hao Li, Dr. Jiashun Zheng and Dr. Chris Fuller at the University of California, San Francisco (UCSF) and Caribou Bioscience. The Li lab grew into a multi-facet research group consist of both experimentalists and computational biologists covering three research areas including cellular/molecular mechanism of ageing, genetic determinants of complex human traits and structure, function, evolution of gene regulatory network. Labs like these are the pillar of global success and reputation
    [Show full text]
  • Uncovering Transcriptional Cis- Regulatory Elements Active in Adult Zebrafish Exocrine Pancreas
    Uncovering transcriptional cis- regulatory elements active in adult zebrafish exocrine pancreas Diogo José Coutinho Ribeiro Dissertação de Mestrado em Bioquímica apresentada à Faculdade de Ciências da Universidade do Porto e Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto 2018 Orientador Dr. José Bessa Principal Investigator, Instituto de Biologia Celular e Molecular / Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal Coorientadores Dra. Renata Bordeira-Carriço Post-Doc Researcher, Instituto de Biologia Celular e Molecular / Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal Prof. Dr. Pedro Rodrigues 1 Associate Professor, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Portugal Todas as correções determinadas Todas as correções determinadas pelo júri, e só essas, foram efetuadas. O Presidente do Júri, Porto, ______/______/_________ This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 680156 - ZPR). Aos meus pais, Ao meu irmão, À memória da minha avó. FCUP/ICBAS Uncovering transcriptional cis-regulatory elements active in adult zebrafish exocrine pancreas Acknowledgments Ao meu Orientador Doutor José Carlos Ribeiro Bessa que me deu a oportunidade de participar neste projeto e, sem a liderança do mesmo, nada do que se segue no presente trabalho teria sido alcançável. Os meus agradecimentos recaem na sua incondicional disponibilidade e apoio em todos os aspetos e momentos, quer a nível profissional, quer pessoal. Por todas as sugestões, motivação, incentivo que se afiguraram fundamentais para o sucesso deste trabalho, bem assim por todo o seu conhecimento inigualável.
    [Show full text]
  • Universita' Degli Studi Di Milano Dna
    UNIVERSITA’ DEGLI STUDI DI MILANO Scuola di Dottorato in Scienze Biomediche Cliniche e Sperimentali Corso di Dottorato in Biotecnologie Applicate alle Scienze Mediche Ciclo XXIV Tesi di dottorato di ricerca DNA METHYLATION AS A PREDISPOSITION FACTOR IN THE PATHOGENESIS OF CONGENITAL HYPOTHYROIDISM IN PRETERM INFANTS Facoltà di Medicina e Chirurgia Settore Scientifico Disciplinare Bio13 Coordinatore: Prof. Enrico GINELLI Tutor: Prof. Luca PERSANI Dottorando: Federica MARELLI Matricola n. R08135 Anno Accademico 2011-2012 Table of contests TABLE OF CONTESTS ................................................................................................................... 2 ABSTRACT ................................................................................................................................... 5 INTRODUCTION-CHAPTER I ......................................................................................................... 7 1. THYROID GLAND DEVELOPMENT AND DEFECTS ...................................................................... 7 1.1 FETAL THYROID DEVELOPMENT: A BRIEF OVERVIEW ............................................................ 7 1.1.1 MORPHOLOGICAL ASPECTS ................................................................................................ 7 1.1.2 GENETIC COMPONENT ON THYROID DEVELOPMENT ....................................................... 10 1.2 THYROID HORMONE METABOLISM AND ACTION ............................................................... 11 1.3 CONGENITAL HYPOTHYROIDISM ........................................................................................
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/0098188 A1 Niculescu Et Al
    US 2011 0098188A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0098188 A1 Niculescu et al. (43) Pub. Date: Apr. 28, 2011 (54) BLOOD BOMARKERS FOR PSYCHOSIS Related U.S. Application Data (60) Provisional application No. 60/917,784, filed on May (75) Inventors: Alexander B. Niculescu, Indianapolis, IN (US); Daniel R. 14, 2007. Salomon, San Diego, CA (US) Publication Classification (51) Int. Cl. (73) Assignees: THE SCRIPPS RESEARCH C40B 30/04 (2006.01) INSTITUTE, La Jolla, CA (US); CI2O I/68 (2006.01) INDIANA UNIVERSITY GOIN 33/53 (2006.01) RESEARCH AND C40B 40/04 (2006.01) TECHNOLOGY C40B 40/10 (2006.01) CORPORATION, Indianapolis, IN (52) U.S. Cl. .................. 506/9: 435/6: 435/7.92; 506/15; (US) 506/18 (57) ABSTRACT (21) Appl. No.: 12/599,763 A plurality of biomarkers determine the diagnosis of psycho (22) PCT Fled: May 13, 2008 sis based on the expression levels in a sample Such as blood. Subsets of biomarkers predict the diagnosis of delusion or (86) PCT NO.: PCT/US08/63539 hallucination. The biomarkers are identified using a conver gent functional genomics approach based on animal and S371 (c)(1), human data. Methods and compositions for clinical diagnosis (2), (4) Date: Dec. 22, 2010 of psychosis are provided. Human blood Human External Lines Animal Model External of Evidence changed in low vs. high Lines of Evidence psychosis (2pt.) Human postmortem s Animal model brai brain data (1 pt.) > Cite go data (1 p. Biomarker For Bonus 1 pt. Psychosis Human genetic 2 N linkage? association A all model blood data (1 pt.) data (1 p.
    [Show full text]
  • Structural Modeling and Functional Characterization of Mammalian Cytosolic Carboxypeptidases 2 and 3
    Structural modeling and functional characterization of mammalian cytosolic carboxypeptidases 2 and 3 Doctoral thesis presented by Olívia Tort Regàs for the degree of PhD in Biochemistry, Molecular Biology and Biomedicine from the Universitat Autònoma de Barcelona Institut de Biotecnologia i Biomedicina Unitat d’Enginyeria de Proteïnes i Proteòmica Thesis supervised by Prof. Francesc Xavier Avilés Puigvert, Dra. Julia Lorenzo Rivera and Dr. Sebastian Tanco Olívia Tort Regàs Prof. Francesc Xavier Dra. Julia Lorenzo Rivera Dr. Sebastian Tanco Avilés Puigvert Barcelona, September 2014 Table of contents TABLE OF CONTENTS LIST OF FIGURES ...................................................................................... 1 LIST OF TABLES ........................................................................................ 3 LIST OF ABBREVIATIONS .......................................................................... 6 PREFACE .................................................................................................. 9 CHAPTER I: INTRODUCTION ................................................................... 12 1 PEPTIDASES ...................................................................................................... 12 1.1 Nomenclature of peptidases ..................................................................................... 12 1.2 Functions of proteolytic enzymes .............................................................................. 13 1.2.1 Proteases in life processes .............................................................................................
    [Show full text]
  • Analysis of Treatment Efficacy and Molecular and Cellular Outcomes In
    Analysis of Treatment Efficacy and Molecular and Cellular Outcomes in Mouse Models of Congenital Epilepsy and Intellectual Disability. Karagh Loring BSc. (Biomedical Science) Hons. Intellectual Disability Laboratory Primary Supervisor: A/Prof Cheryl Shoubridge External Supervisor: A/Prof Quenten Schwarz Thesis submitted for the degree of Doctor of Philosophy in Discipline of Paediatrics, Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide 2020 2 Contents List of Tables .......................................................................................................................... 6 List of Figures ......................................................................................................................... 8 Abstract ................................................................................................................................. 11 Thesis Format ....................................................................................................................... 13 Thesis Declaration ................................................................................................................ 14 Acknowledgments ................................................................................................................ 15 List of Abbreviations ............................................................................................................ 18 Chapter One: The Aristaless-related homeobox gene: understanding its role in intellectual disability and
    [Show full text]
  • Mutation Screening and Imprinting Analysis of Four Candidate Genes For
    Molecular Psychiatry (2002) 7, 289–301 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region E Bonora1, E Bacchelli2, ER Levy1, F Blasi2, A Marlow1, AP Monaco1, E Maestrini2 and the International Molecular Genetic Study of Autism Consortium (IMGSAC)* 1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; 2University of Bologna, Dipartimento di Biologia Evoluzionistica Sperimentale, Bologna, Italy Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify the relevant gene and report the analysis of four adjacent genes localised to a 800 kb region in 7q32 that con- tains an imprinted domain: PEG1/MEST, COPG2, CPA1 and CPA5—a previously uncharacter- ised member of the carboxypeptidase gene family. Screening these genes for DNA changes and association analysis using intragenic single nucleotide polymorphisms (SNPs) provided no evidence for an etiological role in IMGSAC families. We also searched for imprinting mutations potentially implicated in autism: analysis of both DNA methylation and replication timing indicated a normal imprinting regulation of the PEG1/COPG2 domain in blood lympho- cytes of all patients tested. The analysis of these four genes strongly suggests that they do not play a major role in autism aetiology, and delineates our strategy to screen additional candidate genes in the AUTS1 locus. Molecular Psychiatry (2002) 7, 289–301. DOI: 10.1038/sj/mp/4001004 Keywords: autism; candidate genes; mutation screening; methlylation; imprinting; PEG1/MEST; COPG2; carboxypeptidase A; 7q32 Introduction cluster within 7q32.
    [Show full text]
  • Copy Number Abnormalities in Sporadic Canine Colorectal Cancers
    Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Copy number abnormalities in sporadic canine colorectal cancers Jie Tang,1 Shoshona Le,2 Liang Sun,3 Xiuzhen Yan,1 Mucheng Zhang,1 Jennifer MacLeod,4 Bruce LeRoy,5 Nicole Northrup,5 Angela Ellis,5 Timothy J. Yeatman,6 Yanchun Liang,3 Michael E. Zwick,2 and Shaying Zhao1,7 1Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia 30602, USA; 2Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30602, USA; 3College of Computer Science and Technology, Jilin University, Changchun 130021, China; 4School of Veterinary Medicine, University of California Davis, California 95616, USA; 5College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA; 6Departments of Surgery, Pathology, and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a strong degree of genetic homology between sporadic canine and human CRCs. First, we saw that between 5% and 22% of the canine genome was amplified/deleted in these tumors, and that, reminiscent of human CRCs, the total altered sequences directly correlated to the tumor’s progression stage, origin, and likely microsatellite instability status.
    [Show full text]