DOCSLIB.ORG

Identify Metastasis-Associated Genes in Hepatocellular Carcinoma Through Clonality Delineation for Multinodular Tumor1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identify Metastasis-Associated Genes in Hepatocellular Carcinoma Through Clonality Delineation for Multinodular Tumor1 [CANCER RESEARCH 62, 4711–4721, August 15, 2002] Identify Metastasis-associated Genes in Hepatocellular Carcinoma through Clonality Delineation for Multinodular Tumor1 Siu Tim Cheung,2 Xin Chen, Xin Yuan Guan, San Yu Wong, Lai Shan Tai, Irene O. L. Ng, Samuel So, and Sheung Tat Fan Departments of Surgery [S. T. C., S. Y. W., S. T. F.], Clinical Oncology [X. Y. G., L. S. T], Pathology [I. O. L. N.], Centre for the Study of Liver Disease, The University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China, and Departments of Biochemistry [X. C.] and Surgery [S. S.], Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305 ABSTRACT specimens in some cancers. To study clinical metastasis, HCC3 may be the best choice because tumor invasion into blood vessels and Disease recurrence and metastasis are frequently observed in many intrahepatic metastasis are frequently observed and presented as mul- successfully treated localized cancers, including hepatocellular carcinoma tiple nodules at the time of surgical resection (5). in which intrahepatic and extrahepatic recurrence (metastasis) are fre- To identify metastasis-associated genes, the first crucial step is to quently observed after curative resection. The present study aimed at delineate the clonal relationship among the multiple tumor nodules, identifying metastasis-associated genes through delineation of the clonal- ity for multinodular liver cancer. The clonal relationship of 22 tumor foci and to determine which tumor clones were derived from the primary. from six patients was investigated by the genome-wide expression profile However, reliable parameters to define the clonality for multiple via cDNA microarray consisting of 23,000 genes. Tumor molecular prop- nodular HCC have not been established. Conventional discriminations erties including p53 protein overexpression and gene mutation, hepatitis B are mostly based on clinical and pathological findings (5–7), which virus integration pattern, and genetic alteration examined by comparative cannot always provide a definitive answer. Commonly used ap- genomic hybridization were compared. Results indicated that gene expres- proaches include comparison for the HBV integration site to differ- sion patterns could serve as the molecular fingerprint for clonality iden- entiate between intrahepatic metastasis and independent occurrence tification. Together with the molecular data from p53, hepatitis B virus (8–10). However, this is only applicable to HCC with HBV integra- integration and comparative genomic hybridization profiles, tumor nod- tion, whereas tumors related to hepatitis C virus (HCV) or alcohol, ules from five patients were confirmed with clonal relationship, and the which are the common associations in North America (11), cannot be expression profiles of the primary nodules were compared with their validated. Clonal analysis can be examined based on X chromosome corresponding intrahepatic metastatic nodules. A total of 90 clones were inactivation (12, 13), which can be investigated only in female pa- found to be correlated with intrahepatic metastasis by Student’s t test tients. In East Asia, including Hong Kong, HCC patients are predom- (P < 0.05). With reference to the primary tumor, 63 clones (39 known inantly male; thus, the approach based on X chromosome inactivation genes and 24 express sequence tags) were down-regulated whereas 27 clones (14 known genes and 13 express sequence tags) were up-regulated does not have a wide implication. DNA fingerprinting (14) and in the metastatic nodules. These metastasis-associated genes may provide fractional allelic loss (15) analysis have also been used for clonality clues to reveal patients with increased risk of developing metastasis, and studies. However, the demanding technique involved combined with to identify novel therapeutic targets for the treatment of metastasis. the problem of reproducibility and the subjective data analysis all hinder their wide application in clonality examination. In a recent study, we used the cDNA microarray approach to INTRODUCTION examine the genome-wide expression profile of over 200 samples consisting of majority HCC and the tumor adjacent liver tissues (16). Metastasis is the major cause of cancer morbidity and mortality. A consistent expression difference was observed between the tumors Comprehensive analysis of gene expression profiles between a pri- and their adjacent nontumor livers. To investigate whether the expres- mary tumor and its derived tumors can identify differential genes sion profile can help to elucidate the clonal relationship of the multi- associated with the metastatic phenotype, which help to elucidate the nodular liver cancers, samples from individual tumor foci were further molecular mechanism of cancer metastasis (1, 2). There are a number examined with the conventional molecular genetic approach for tumor of experimental models for the examination of genes responsible for properties and genetic aberrations. The expression data of 22 individ- the enhancement or suppression of cancer metastasis (3, 4). However, ual tumor foci in six patients with multinodular HCC were compared the clinical relevance of these genes is sometimes difficult to consol- with the conventional molecular genetic data including p53 protein idate. The most direct method to identify genes associated with overexpression and p53 gene mutation, HBV integration, and genetic clinical metastasis is to examine the human specimens, and to com- aberrations as investigated by CGH. The data up until now had pare the primaries with their corresponding metastatic tumors. Sample suggested that gene expression profiles were unique for each tumor availability can be the major hurdle, as reflected in the long time and could provide sufficient information to delineate clonal relation- interval between the primaries and the appearance of secondaries. The ships. The identity of primary and intrahepatic metastasis tumor tumor type or anatomical site may not allow for the collection of nodules was further confirmed by conventional molecular genetic approaches, and the expression profiles of the original and metastatic Received 1/28/02; accepted 6/13/02. tumor clones were compared with those of the genes associated with The costs of publication of this article were defrayed in part by the payment of page intrahepatic metastases. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by grants from the Sun Chieh-Yeh Research Foundation for Hepatobiliary and Pancreatic Surgery, and Seed Funding Programme, The University of MATERIALS AND METHODS Hong Kong (to S. T. C. and S. T. F.), and H. M. Liu Foundation, Stanford University (to X. C. and S. S.), and a fellowship from Howard Hughes of the Life Science Research Patients and Samples. Informed consent was obtained from the patients Foundation, Stanford University (to X. C.). for the collection of liver specimens, and the study protocol was approved by 2 To whom requests for reprints should be addressed, at Department of Surgery, Centre for the Study of Liver Disease, The University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China. Phone: 852-2855-3995; Fax: 852-2818-4407; E-mail: 3 The abbreviations used are: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; [email protected]. CGH, comparative genomic hybridization; EMP3, epithelial membrane protein 3. 4711 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2002 American Association for Cancer Research. METASTASIS-ASSOCIATED GENES IN LIVER CANCER the Ethics Committee of The University of Hong Kong. Between April and washes, and incubation with anti-fluorescein-horseradish peroxidase conjugate, July 2000, six patients with multiple nodular liver tumors were treated by ECL detection reagent (Amersham Pharmacia Biotech) was used, and a signal was surgical resection (Table 1). A total of 22 samples were obtained from developed by X-Omat AR film (Kodak, Rochester, NY). individual tumor foci of the surgical specimens. Samples were snap-frozen in CGH. Protocols have been established and details described previously liquid nitrogen and stored at Ϫ70°C until use. Paralleled tumor specimens (26, 27). In brief, DNA from tumor and normal reference were labeled with were formalin fixed and paraffin embedded for histological examination and different fluorescent dUTPs by nick translation. Labeled probes were mixed immunohistochemical study. Total RNA was extracted with RNeasy kit (Qia- and hybridized onto metaphase cells prepared from the lymphocytes of healthy gen, Hilden, Germany) and mRNA was isolated from total RNA using Fast- donors. The slide was counterstained with 4Ј,6-diamidino-2-phenylindole di- Track (Invitrogen, Carlsbad, CA) or Poly(A)Pure (Ambion, Inc., Austin, TX) hydrochloride (DAPI) for digital image analysis using the Quips CGH program mRNA purification kit. DNA was extracted with DNAeasy kit (Qiagen) (Vysis, Downers Grove, IL). The thresholds used for the interpretation of gains according to the manufacturer’s instructions. and losses of a DNA sequence copy number were defined as the tumor: Microarray Expression Study. The cDNA microarray slides were printed reference ratio and were Ͼ1.25 and Ͻ0.75, respectively. The thresholds with 23,075 cDNA clones. Protocols have been established and the details applied for both the standard and the reverse hybridization
Load more

Recommended publications
  • Download The
    PROBING THE INTERACTION OF ASPERGILLUS FUMIGATUS CONIDIA AND HUMAN AIRWAY EPITHELIAL CELLS BY TRANSCRIPTIONAL PROFILING IN BOTH SPECIES by POL GOMEZ B.Sc., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Pol Gomez, 2010 ABSTRACT The cells of the airway epithelium play critical roles in host defense to inhaled irritants, and in asthma pathogenesis. These cells are constantly exposed to environmental factors, including the conidia of the ubiquitous mould Aspergillus fumigatus, which are small enough to reach the alveoli. A. fumigatus is associated with a spectrum of diseases ranging from asthma and allergic bronchopulmonary aspergillosis to aspergilloma and invasive aspergillosis. Airway epithelial cells have been shown to internalize A. fumigatus conidia in vitro, but the implications of this process for pathogenesis remain unclear. We have developed a cell culture model for this interaction using the human bronchial epithelium cell line 16HBE and a transgenic A. fumigatus strain expressing green fluorescent protein (GFP). Immunofluorescent staining and nystatin protection assays indicated that cells internalized upwards of 50% of bound conidia. Using fluorescence-activated cell sorting (FACS), cells directly interacting with conidia and cells not associated with any conidia were sorted into separate samples, with an overall accuracy of 75%. Genome-wide transcriptional profiling using microarrays revealed significant responses of 16HBE cells and conidia to each other. Significant changes in gene expression were identified between cells and conidia incubated alone versus together, as well as between GFP positive and negative sorted cells.
    [Show full text]
  • Transcriptome-Wide Association Study Identifies Susceptibility Genes For
    Wu et al. Arthritis Research & Therapy (2021) 23:38 https://doi.org/10.1186/s13075-021-02419-9 RESEARCH ARTICLE Open Access Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis Cuiyan Wu*, Sijian Tan, Li Liu, Shiqiang Cheng, Peilin Li, Wenyu Li, Huan Liu, Feng’e Zhang, Sen Wang, Yujie Ning, Yan Wen and Feng Zhang* Abstract Objective: To identify rheumatoid arthritis (RA)-associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression profile data. Methods: A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed fibroblasts (TF), peripheral blood (NBL), and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identified genes were further validated using the mRNA expression profiles and made a functional exploration. EL TF NBL Results: TWAS identified 692 genes with PTWAS values < 0.05 for RA. CRIPAK (P = 0.01293, P = 0.00038, P = 0.02839, PYBL = 0.0978), MUT (PEL = 0.00377, PTF = 0.00076, PNBL = 0.00778, PYBL = 0.00096), FOXRED1 (PEL = 0.03834, PTF = 0.01120, PNBL = 0.01280, PYBL = 0.00583), and EBPL (PEL = 0.00806, PTF = 0.03761, PNBL = 0.03540, PYBL = 0.04254) were collectively expressed in all the four tissues/cells. Eighteen genes, including ANXA5, AP4B1, ATIC (PTWAS = 0.0113, downregulated expression), C12orf65, CMAH, PDHB, RUNX3 (PTWAS = 0.0346, downregulated expression), SBF1, SH2B3, STK38, TMEM43, XPNPEP1, KIAA1530, NUFIP2, PPP2R3C, RAB24, STX6, and TLR5 (PTWAS = 0.04665, upregulated expression), were validated with integrative analysis of TWAS and mRNA expression profiles.
    [Show full text]
  • Insights Into MYC Biology Through Investigation of Synthetic Lethal Interactions with MYC Deregulation
    Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Mai Sato All Rights Reserved ABSTRACT Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation Mai Sato MYC (or c-myc) is a bona fide “cancer driver” oncogene that is deregulated in up to 70% of human tumors. In addition to its well-characterized role as a transcription factor that can directly promote tumorigenic growth and proliferation, MYC has transcription-independent functions in vital cellular processes including DNA replication and protein synthesis, contributing to its complex biology. MYC expression, activity, and stability are highly regulated through multiple mechanisms. MYC deregulation triggers genome instability and oncogene-induced DNA replication stress, which are thought to be critical in promoting cancer via mechanisms that are still unclear. Because regulated MYC activity is essential for normal cell viability and MYC is a difficult protein to target pharmacologically, targeting genes or pathways that are essential to survive MYC deregulation offer an attractive alternative as a means to combat tumor cells with MYC deregulation. To this end, we conducted a genome-wide synthetic lethal shRNA screen in MCF10A breast epithelial cells stably expressing an inducible MYCER transgene. We identified and validated FBXW7 as a high-confidence synthetic lethal (MYC-SL) candidate gene. FBXW7 is a component of an E3 ubiquitin ligase complex that degrades MYC. FBXW7 knockdown in MCF10A cells selectively induced cell death in MYC-deregulated cells compared to control.
    [Show full text]
  • Universidade De São Paulo Faculdade De Medicina De Ribeirão Preto Departamento De Genética
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO DEPARTAMENTO DE GENÉTICA TATIANA MOZER JOAQUIM CORRELAÇÃO CARIÓTIPO-GENÓTIPO-FENÓTIPO DE REARRANJO CROMOSSÔMICO ESTRUTURAL FAMILIAR ENVOLVENDO AS REGIÕES 4p E 12q RIBEIRÃO PRETO – SP 2016 TATIANA MOZER JOAQUIM CORRELAÇÃO CARIÓTIPO-GENÓTIPO-FENÓTIPO DE REARRANJO CROMOSSÔMICO ESTRUTURAL FAMILIAR ENVOLVENDO AS REGIÕES 4p E 12q Dissertação apresentada à Universidade de São Paulo, como requisito para obtenção do título de Mestre, pelo curso de Pós-graduação em Genética da Faculdade de Medicina de Ribeirão Preto. Área de concentração: Genética Orientadora: Profa. Dra. Lucia Regina Martelli RIBEIRÃO PRETO – SP 2016 Autorizo a reprodução e divulgação total ou parcial deste trabalho, por qualquer meio convencional ou eletrônico, para fins de estudo e pesquisa, desde que citada a fonte. FICHA CATALOGRÁFICA Joaquim, Tatiana Mozer Correlação cariótipo-genótipo-fenótipo de rearranjo cromossômico estrutural familiar envolvendo as regiões 4p e 12q. Ribeirão Preto, São Paulo, 2016. 135p: il;30cm. Dissertação de Mestrado, apresentada à Faculdade de Medicina de Ribeirão Preto/USP – Área de concentração: Genética. Orientadora: Martelli, Lucia 1. Citogenética; 2. Translocação cromossômica; 3. Derivativo de 4; 4. FISH; 5. Citogenômica; 6. array-CGH FOLHA DE APROVAÇÃO Nome: Tatiana Mozer Joaquim Título: Correlação cariótipo-genótipo-fenótipo de rearranjo cromossômico estrutural familiar envolvendo as regiões 4p e 12q Dissertação apresentada à Universidade de São Paulo, como requisito para obtenção do título de Mestre, pelo curso de Pós-graduação em Genética da Faculdade de Medicina de Ribeirão Preto. Área de concentração: Genética Orientadora: Profa. Dra. Lucia Regina Martelli Aprovada em: _______|_______|_______ BANCA EXAMINADORA Prof. Dr.:___________________________________________________________________ Julgamento:_______________________ Assinatura:________________________________ Prof.
    [Show full text]
  • Single-Molecule Studies of Rad4-Rad23 Reveal a Dynamic Dna Damage Recognition Process
    SINGLE-MOLECULE STUDIES OF RAD4-RAD23 REVEAL A DYNAMIC DNA DAMAGE RECOGNITION PROCESS by Muwen Kong B.A. Physics, Knox College, 2008 M.S. Physics, Carnegie Mellon University, 2010 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2017 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Muwen Kong It was defended on June 30, 2017 and approved by Guillermo Romero, PhD., Associate Professor, Department of Pharmacology and Chemical Biology Marcel Bruchez, PhD., Associate Professor, Departments of Biological Sciences and Chemistry, Carnegie Mellon University Neil Kad, PhD., Senior Lecturer, School of Biosciences, University of Kent Patricia Opresko, PhD., Associate Professor, Department of Environmental and Occupational Health Dissertation Director: Bennett Van Houten, PhD., Professor, Department of Pharmacology and Chemical Biology ii Copyright © by Muwen Kong 2017 iii Single-Molecule Studies of Rad4-Rad23 Reveal a Dynamic DNA Damage Recognition Process Muwen Kong, PhD University of Pittsburgh, 2017 Nucleotide excision repair (NER) is an evolutionarily conserved mechanism that processes helix- destabilizing and/or -distorting DNA lesions, such as UV-induced photoproducts. As the first step towards productive repair, the human NER damage sensor XPC-RAD23B needs to efficiently locate sites of damage among billons of base pairs of undamaged DNA. In this dissertation, we investigated the dynamic protein-DNA interactions during the damage recognition step using a combination of fluorescence-based single-molecule DNA tightrope assays, atomic force microscopy, as well as cell survival and in vivo repair kinetics assays. We observed that quantum dot-labeled Rad4-Rad23, the yeast homolog of human XPC-RAD23B, formed nonmotile complexes on DNA or conducted a one-dimensional search via either random diffusion or constrained motion along DNA.
    [Show full text]
  • Francine Blumental De Abreu
    VARIAÇÃO NO NÚMERO DE CÓPIAS GENÔMICAS NA AVALIAÇÃO DE GENES PRINCIPAIS DE PREDISPOSIÇÃO EM PACIENTES COM SÍNDROME DE MAMA-CÓLON TRIADOS PARA MUTAÇÕES NOS GENES BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 FRANCINE BLUMENTAL DE ABREU Tese apresentada à Fundação Antônio Prudente para obtenção do Título de Doutor em Ciências Área de concentração: Oncologia Orientadora: Profª Dra. Silvia Regina Rogatto São Paulo 2012 FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Abreu, Francine Blumental de Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com síndrome de mama- cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 / Francine Blumental de Abreu – São Paulo, 2012. 245p. Tese (Doutorado)-Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia. Orientadora: Silvia Regina Rogatto Descritores: 1. SÍNDROME DE LYNCH. 2. NEOPLASIAS DA MAMA. 3. VARIAÇÃO DO NÚMERO DE CÓPIA DO DNA. 4. HIBRIDIZAÇÃO GENÔMICA COMPARATIVA. DEDICATÓRIA A minha família!!!! AGRADECIMENTOS À minha família... Edilucia (II:5) e Antonio (II:6) por serem mais do que pais, por serem mais do que amigos, por serem os meus super heróis! Obrigada pelos abraços, pelas palavras de apoio e de ensinamento, pelo carinho, pelo amor incondicional! Obrigada por estarem sempre disponíveis, por estenderem as mãos depois de uma “rasteira” da vida, por enxugarem as minhas lágrimas! Obrigada principalmente por me fazerem acreditar que momentos difíceis existem,
    [Show full text]
  • Diseases Associated with Defective Responses to DNA Damage
    Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diseases Associated with Defective Responses to DNA Damage Mark O’Driscoll Human DNA Damage Response Disorders Group Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, United Kingdom Correspondence: [email protected] Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identi- fied, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways. he link between DNA damage, mutagenesis, sense XP represents a paradigm of a DNA repair Tand malignant transformation is long estab- disorder with a clear pathological link between lished. A logical extension is that a congenital genotype and phenotype (Cleaver et al. 2009). defect in a fundamental DNA repair pathway, As our knowledge of the complexity of ge- such as nucleotide excision repair (NER), would nome stability pathways has evolved, coupled be anticipated to be associated with a pro- with the explosive technical advances in molec- nounced cancer predisposition syndrome.
    [Show full text]
  • International Genome-Wide Association Study Consortium Identifies Novel Loci Associated with Blood Pressure in Children and Adolescents
    Original Article International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents Priyakumari Ganesh Parmar, PhD; H. Rob Taal, MD, PhD; Nicholas J. Timpson, PhD; Elisabeth Thiering, PhD*; Terho Lehtimäki, MD, PhD*; Marcella Marinelli, PhD*; Penelope A. Lind, PhD*; Laura D. Howe, PhD; Germaine Verwoert, PhD; Ville Aalto, MSc; Andre G. Uitterlinden, PhD; Laurent Briollais, PhD; Dave M. Evans, PhD; Margie J. Wright, PhD; John P. Newnham, MD; John B. Whitfield, PhD; Leo-Pekka Lyytikäinen, MD; Fernando Rivadeneira, MD, PhD; Dorrett I. Boomsma, PhD; Jorma Viikari, MD, PhD; Matthew W. Gillman, MD, SM; Beate St Pourcain, PhD; Jouke-Jan Hottenga, PhD; Grant W. Montgomery, PhD; Albert Hofman, MD, PhD; Mika Kähönen, MD, PhD; Nicholas G. Martin, PhD; Martin D. Tobin, PhD; Ollie Raitakari, MD, PhD; Jesus Vioque, MD, PhD; Vincent W.V. Jaddoe, MD, PhD; Marjo-Riita Jarvelin, MD, PhD; Lawrence J. Beilin, MD; Joachim Heinrich, PhD; Cornelia M. van Duijn, PhD; Craig E. Pennell, MD, PhD; Debbie A. Lawlor, MD, PhD†; Lyle J. Palmer, PhD†; Early Genetics and Lifecourse Epidemiology Consortium Background—Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Methods and Results—Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4–7 years), puberty (8–12 years), and postpuberty (13–20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5′-C-phosphate-G-3′ methylation site) during prepuberty (P=2.86×10–8) and rs872256 during puberty (P=8.67×10–9).
    [Show full text]
  • Transcriptome-Wide Association Study Identi Es Susceptibility Genes For
    Transcriptome-wide association study identies susceptibility genes for rheumatoid arthritis Cuiyan Wu ( [email protected] ) Xi'an Jiaotong University Health and Science Center Sijia Tan Xi'an Jiaotong University Li Liu Xi'an Jiaotong University Shiqiang Cheng Xi'an Jiaotong University Peilin Li Xi'an Jiaotong University Wenyu Li Xi'an Jiaotong University Huan Liu Xi'an Jiaotong University Feng'e Zhang Xi'an Jiaotong University Sen Wang Xi'an Jiaotong University Yujie Ning Xi'an Jiaotong University Yan Wen Xi'an Jiaotong University Feng Zhang Xi'an Jiaotong University Research article Keywords: rheumatoid arthritis (RA), transcriptome-wide association study (TWAS), genome wide association study (GWAS), susceptibility genes Posted Date: October 8th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-86447/v1 Page 1/16 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on January 22nd, 2021. See the published version at https://doi.org/10.1186/s13075-021-02419-9. Page 2/16 Abstract Objective To identify rheumatoid arthritis (RA) associated susceptibility genes and pathways through integrating genome-wide association study (GWAS) and gene expression prole data. Methods A transcriptome-wide association study (TWAS) was conducted by the FUSION software for RA considering EBV-transformed lymphocytes (EL), transformed broblasts (TF), peripheral blood (NBL) and whole blood (YBL). GWAS summary data was driven from a large-scale GWAS, involving 5,539 autoantibody-positive RA patients and 20,169 controls. The TWAS-identied genes were further validated using the mRNA expression proles and made a functional exploration.
    [Show full text]
  • Anti-USP7 / HAUSP Antibody (ARG59189)
    Product datasheet [email protected] ARG59189 Package: 50 μg anti-USP7 / HAUSP antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes USP7 / HAUSP Tested Reactivity Hu, Ms, Rat Tested Application FACS, ICC/IF, IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name USP7 / HAUSP Species Human Immunogen Recombinant protein corresponding to L258-D483 of Human USP7 / HAUSP. Conjugation Un-conjugated Alternate Names Ubiquitin-specific-processing protease 7; Ubiquitin carboxyl-terminal hydrolase 7; HAUSP; Herpesvirus- associated ubiquitin-specific protease; Deubiquitinating enzyme 7; TEF1; Ubiquitin thioesterase 7; EC 3.4.19.12 Application Instructions Application table Application Dilution FACS 1:150 - 1:500 ICC/IF 1:200 - 1:1000 IHC-P 0.5 - 1 µg/ml WB 0.1 - 0.5 µg/ml Application Note IHC-P: Antigen Retrieval: Heat mediation was performed in Citrate buffer (pH 6.0) for 20 min. * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Properties Form Liquid Purification Affinity purification with immunogen. Buffer 0.9% NaCl, 0.2% Na2HPO4, 0.05% Sodium azide and 4% Trehalose. Preservative 0.05% Sodium azide Stabilizer 4% Trehalose Concentration 0.5 - 1 mg/ml Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated www.arigobio.com 1/4 freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use.
    [Show full text]
  • Mammalian Transcription-Coupled Excision Repair
    Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Mammalian Transcription-Coupled Excision Repair Wim Vermeulen1 and Maria Fousteri2 1Department of Genetics and Netherlands Proteomics Centre, Centre for Biomedical Genetics, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands 2Institute of Molecular Biology and Genetics, Biomedical Sciences Research Centre Alexander Fleming, 16672 Athens, Greece Correspondence: fousteri@fleming.gr Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcrip- tional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients’ death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process. amaged DNA causes genome instability demands alternative strategies to deal with these Dand reduces the fidelity of the replication genomic road blocks. Additional key repair pro- process, resulting in increased mutagenesis, cesses exist to prevent replication fork collapse which are both at the basis of oncogenic trans- and promote fork restart (e.g., translesion syn- formation. In addition, lesions may block tran- thesis and homologous recombination) or to scription, which causes disturbed cellular ho- resolve stalled transcription (transcription-cou- meostasis and may trigger cellular senescence pled nucleotide excision repair; TC-NER).
    [Show full text]
  • Galaxy, a Web-Based Framework for the Integration of Genome Analysis
    The Pennsylvania State University The Graduate School Eberly College of Science GALAXY, A WEB-BASED FRAMEWORK FOR THE INTEGRATION OF GENOME ANALYSIS A Dissertation in Biochemistry, Microbiology and Molecular Biology by Daniel James Blankenberg © 2009 Daniel James Blankenberg Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2009 The dissertation of Daniel James Blankenberg was reviewed and approved* by the following: Anton Nekrutenko Associate Professor of Biochemistry and Molecular Biology Dissertation Adviser Chair of Committee Webb C. Miller Professor of Biology Professor of Computer Science and Engineering Ross C. Hardison T. Ming Chu Professor of Biochemistry and Molecular Biology Stephan Schuster Professor of Biochemistry and Molecular Biology Andrey Krasilnikov Assistant Professor of Biochemistry and Molecular Biology Scott Selleck Professor of Biochemistry and Molecular Biology Head of the Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School. ii ABSTRACT The standardization and sharing of data and tools are among the biggest challenges facing large collaborative projects and small individual labs alike. Here a compact web application, Galaxy, is described which effectively addresses these issues. It provides an intuitive interface for the deposition and access of data and features a vast number of analysis tools including operations on genomic intervals, utilities for manipulation of multiple sequence alignments and molecular evolution algorithms. By providing a direct link between data and analysis tools, Galaxy allows addressing biological questions that are beyond the reach of existing software. Available both as (1) a publicly available web service providing tools for the analysis of genomic, comparative genomic and functional genomic data and (2) a downloadable package that can be deployed in individual labs, Galaxy attempts to serve both sides of the user distribution: experimental biologists and bioinformaticians.
    [Show full text]