DOCSLIB.ORG

Global Dna Methylation and Gene Expression Analysis in Pre-B Cell Acute Lymphoblastic Leukemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Global Dna Methylation and Gene Expression Analysis in Pre-B Cell Acute Lymphoblastic Leukemia GLOBAL DNA METHYLATION AND GENE EXPRESSION ANALYSIS IN PRE-B CELL ACUTE LYMPHOBLASTIC LEUKEMIA A Dissertation presented to the Faculty of the Graduate School at the University of Missouri-Columbia In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy by MD ALMAMUN Dr. Kristen H. Taylor, Dissertation Supervisor JULY 2015 © Copyright by Md Almamun 2015 All Rights Reserved The undersigned, appointed by the dean of the Graduate School, have examined the Dissertation entitled GLOBAL DNA METHYLATION AND GENE EXPRESSION ANALYSIS IN PRE-B CELL ACUTE LYMPHOBLASTIC LEUKEMIA Presented by Md Almamun A candidate for the degree of Doctor of Philosophy And hereby certify that, in their opinion, it is worthy of acceptance. Kristen H. Taylor James M. Amos-Landgraf Gerald L. Arthur Mark A. Daniels J. Wade Davis DEDICATION This work is dedicated to my parents, Abdul Aziz & Khosh Nahar Begum, my inspiration. ACKNOWLEDGMENTS I would first like to acknowledge my advisor, Dr. Kristen H. Taylor for her guidance and patience throughout this research project. I was able to gain knowledge, research passion and complete this project with her tremendous helps and encouragement. Thank you for being so positive and for everything you did for me. I would also like to thank my degree committee members, Dr. J. Wade Davis, Dr. Gerald L. Arthur, Dr. James M. Amos-Landgraf, and Dr. Mark A. Daniels for their advice and guidance in this endeavor. I would like to special thank Dr. J. Wade Davis, Benjamin T. Levinson, and Nathan T. Johnson for analyzing MIRA-seq and RNA-seq data, and Annette C. van Swaay for helping me during data analysis. Thank to Dr. Stephanie D. McKay for her advice during method development. I would like to thank the members of the Taylor Lab, specifically Ambima H. Buzhyason, Alexei J. Stuckel, and Darren C. Hawkins for being so nice to me and for your suggestions in different aspects of my research works. I have truly enjoyed every day because of the great people in Dr. Taylor’s Lab. Finally, I would like to thank my parents, my wife Fauzia Huq Nur, and other family members for always supporting me. I could not have done any of this work without their support, love and encouragement. ii TABLE OF CONTENTS ACKNOWLEDGMENTS……………………………………………………………………...…ii LIST OF TABLES …………………………………………………………………………......viii LIST OF FIGURES………………………………………………………………………………ix LIST OF ABBREVIATIONS…………………………………………………………………...xii ABSTRACT…………………………………………………………………………………….xiii Chapter Page CHAPTER 1: INTRODUCTION ………………………………………………………………...1 TABLES AND FIGURES ………………………………………………………………..9 REFERENCES ………………………………………………………………………….11 CHAPTER 2: BACKGROUND…………………………………………………………………15 2.1 ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)…………………………………15 2.1.1 ALL induction mechanisms ……………………………………………….15 2.1.2 ALL classifications ………………………………………………………..16 2.1.3 ALL treatments and prognosis …………………………………………….18 2.1.3.1 Diagnosis ………………………………………………………...18 2.1.3.2 Treatment ………………………………………………………..20 2.1.3.3 Prognosis ………………………………………………………...23 2.2 NORMAL B-CELL DEVELOPMENT ……………………………………………..24 2.3 EPIGENETICS ……………………………………………………………………...27 2.4 DNA METHYLATION ……………………………………………………………..28 2.4.1 DNA methyltransferases …………………………………………………..30 2.4.2 DNA methylation in normal development including B-cell developments.34 2.4.3 DNA methylation in cancer ……………………………………………….36 iii 2.4.4 DNA methylation as a biomarkers for diagnosis ………………………….39 2.4.5 DNA methylation inhibitors for cancer treatment ………………………...42 2.4.6 Methods for DNA methylation studies ……………………………………44 2.5 HISTONE MODIFICATIONS ……………………………………………………...46 2.6 LINC-RNA ………………………………………………………………………….47 2.7 MICRO-RNA ………………………………………………………………………..49 2.7.1 MicroRNA in B-cell development ………………………………………...49 2.7.2 MicroRNA in cancer ………………………………………………………50 2.8 PSEUDOGENES ……………………………………………………………………52 2.9 GENOMIC REGULATORY REGIONS …………………………………………...55 2.9.1 Promoter regions …………………………………………………………..56 2.9.2 Enhancer regions …………………………………………………………..56 2.9.3 Dnase I hypersensitive site (DHS) ………………………………………...59 2.9.4 Transposable elements …………………………………………………….60 2.9.5 CpG islands ………………………………………………………………..62 TABLES AND FIGURES ………………………………………………………………63 REFERENCES ………………………………………………………………………….67 CHAPTER 3: ISOLATION OF PRECURSOR-B CELL SUBSETS FROM HUMAN UMBILICAL CORD BLOOD ………………………………………………………………….88 3.1 ABSTRACT.………………………………………………………………………...88 3.2 INTRODUCTION …………………………………………………………………..89 3.3 PROTOCOL ………………………………………………………………………...91 3.3.1 Isolation of mononuclear cells from umbilical cord blood…………….......91 iv 3.3.2 Modified B-cell isolation procedure from mononuclear cells using MACS separation ………………………………………………………………..92 3.3.3 Antibody labeling and preparation for cell sorting ………………………..94 3.3.4 Cell sorting using the MoFlo XDP flow cytometer ……………………….94 3.4 REPRESENTATIVE RESULTS ……………………………………………………96 3.5 DISCUSSION ……………………………………………………………………….96 TABLES AND FIGURES ……………………………………………………………..100 REFERENCES ………………………………………………………………………...106 CHAPTER 4: GENOME-WIDE DNA METHYLATION ANALYSIS IN PRECURSOR B-CELLS ………………………………………………………………………………………108 4.1 ABSTRACT ……………………………………………………………………….108 4.2 INTRODUCTION …………………………………………………………………109 4.3 MATERIALS AND METHODS …………………………………………………..111 4.3.1 Isolation of precursor B-cell subsets ……………………………………..111 4.3.2 DNA isolation and MIRA-seq library preparation ………………………111 4.3.3 Data processing, alignment, and peak identification …………………….113 4.3.4 Annotation and enhancer prediction ……………………………………..114 4.3.5 Differentially methylated regions of interest …………………………….114 4.4 RESULTS ………………………………………………………………………….116 4.4.1 Genomic distribution of DNA methylation during B-cell development…116 4.4.2 Differentially methylated regions in precursor B-cell differentiation……117 4.5 DISCUSSION ……………………………………………………………………...119 TABLES AND FIGURES ……………………………………………………………..122 REFERENCES ………………………………………………………………………...131 v CHAPTER 5: INTEGRATED METHYLOME AND TRANSCRIPTOME ANALYSIS REVEALS NOVEL REGULATORY ELEMENTS IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA …………………………………………………………….134 5.1 ABSTRACT ………………………………………………………………………..134 5.2 INTRODUCTION …………………………………………………………………135 5.3 MATERIALS AND METHODS …………………………………………………..136 5.3.1 Patient samples …………………………………………………………...136 5.3.2 Antibodies ………………………………………………………………..137 5.3.2 MIRA-seq library preparation ……………………………………………137 5.3.3 Identification of methylated peaks and differentially methylated regions in ALL ……………………………………………………………138 5.3.4 Annotation and enhancer prediction ……………………………………..139 5.3.5 RNA-seq library preparation and data analysis ………………………….140 5.4 RESULTS ………………………………………………………………………….141 5.4.1 Genome-wide DNA methylation profiles ………………………………..141 5.4.2 Differentially methylated regions in ALL ……………………………….141 5.4.3 B-cell development genes and epigenetic modifiers are aberrantly expressed in ALL …………………………………………………………145 5.4.4 Differential expression of transcripts with epigenetic regulatory functions ………………………………………………………………….146 5.5 DISCUSSION ……………………………………………………………………...148 TABLES AND FIGURES …………………………….……………………………….152 REFERENCES ……………………………………………………………………..167 vi CHAPTER 6: TRANSCRIPTIONAL INACTIVATION OF REGULATORY ENHANCERS ASSOCIATED WITH THE MIS-REGULATION OF NEIGHBORING GENES……………171 6.1 ABSTRACT ………………………………………………………………………..171 6.2 INTRODUCTION …………………………………………………………………172 6.2 MATERIALS AND METHODS …………………………………………………..175 6.2.1 ChIP-seq data …………………………………………………………….175 6.3.2 RNA-seq data …………………………………………………………….175 6.3.3 Differentially methylated regions between ALL and healthy pre-B cell...176 6.3 RESULTS ………………………………………………………………………….176 6.3.1 Enhancer identification in normal B lymphocytes (GM12878)………….176 6.3.2 Alteration of Enhancer methylation in ALL ……………………………..177 6.3.3 Enhancer transcript (eRNA) associated with the expression of neighboring genes ………………………………………………………...179 6.4 DISCUSSION ……………………………………………………………………...183 TABLES AND FIGURES …………………………………………………………188 REFERENCES …………………………………………………………………….201 CHAPTER 7: SUMMARY AND FUTURE DIRECTIONS ………………………………….206 REFERENCES…………………………………………………………………………217 VITA …………………………………………………………………………………………..220 vii LIST OF TABLES Table Page 2.1: Epigenetic aberrations among different tumor types………………………………………..64 3.1: Representative cell sort statistics…………………………………………………………..100 3.2: Sorted subsets of B-cell from human umbilical cord blood……………………………….104 4.1: Read and alignment statistics for individual samples ……………………………………123 4.2: Differentially methylated enhancer target genes involved in leukocyte activation and BCR signaling pathway ……………………………………………………………….130 5.1: Pre-B ALL patients characteristics ………………………………………………………..152 5.2: Illumina sequencing data for MIRA-seq ……………………………………………...…..153 5.3: Gene promoter hypermethylation associated with significant decreased expression in ALL …………………………………………………………………………159 5.4: Gene promoter hypomethylation associated with significant increased expression in ALL …………………………………………………………………………160 5.5: Differentially expressed genes in ALL involved in B-cell development and epigenetic modifications …………………………………………………………………..162 5.6: Up-regulated lincRNA in ALL ……………………………………………………………164 5.7: Down-regulated lincRNA in ALL ………………………………………………………...165 6.1: Significantly up-regulated genes related with the hypomethylation of poised enhancers in ALL …………………………………………………………………………………….192 6.2: Significantly up-regulated genes related with the hypomethylation of poised enhancers in ALL …………………………………………………………………………193
Load more

Recommended publications
  • Anti-HSPA9 Antibody
    FOR RESEARCH USE ONLY! 09/19 Anti-HSPA9 Antibody CATALOG NO.: A1861-100 100 µl. BACKGROUND DESCRIPTION: This gene encodes a member of the heat shock protein 70 gene family. The encoded protein is primarily localized to the mitochondria but is also found in the endoplasmic reticulum, plasma membrane and cytoplasmic vesicles. This protein is a heat-shock cognate protein. This protein plays a role in cell proliferation, stress response and maintenance of the mitochondria. A pseudogene of this gene is found on chromosome 2. ALTERNATE NAMES: CSA, PBP74, MOT, MTHSP75, SAAN, HSPA9, HSPA9B, SIDBA4, mitochondrial, EVPLS, CRP40 . ANTIBODY TYPE: Polyclonal HOST/ISOTYPE: Rabbit / Rabbit IgG. IMMUNOGEN: Recombinant fusion protein containing a sequence corresponding to amino acids 380-679 of human HSPA9 (NP_004125.3). PURIFICATION: Affinity purification. FORM: Liquid. FORMULATION: Buffer: PBS with 0.02% sodium azide, 50% glycerol, pH7.3. SPECIES REACTIVITY: Rat. Mouse. Human. STORAGE CONDITIONS: Store at -20°C; Avoid freeze / thaw cycles. APPLICATIONS AND USAGE: IF 1:50 - 1:200. WB 1:500 - 1:2000. IHC 1:50 - 1:200. Immunofluorescence analysis of U2OS cells using HSPA9 antibody. Blue: DAPI for nuclear staining.. Immunohistochemistry of paraffin-embedded rat kidney using HSPA9 antibody at dilution of 1:100. 155 S. Milpitas Blvd., Milpitas, CA 95035 USA | T: (408)493-1800 F: (408)493-1801 | www.biovision.com | [email protected] FOR RESEARCH USE ONLY! Immunohistochemistry of paraffin-embedded human lung cancer using HSPA9 antibody at dilution of 1:100 Immunohistochemistry of paraffin-embedded mouse heart using HSPA9 antibody at dilution of 1:100 Immunohistochemistry of paraffin-embedded human gastric cancer using HSPA9 antibody at dilution of 1:100 Western blot analysis of extracts of various cell lines, using HSPA9 antibody at 1:1000 dilution.
    [Show full text]
  • Genome-Wide Analysis of 5-Hmc in the Peripheral Blood of Systemic Lupus Erythematosus Patients Using an Hmedip-Chip
    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 35: 1467-1479, 2015 Genome-wide analysis of 5-hmC in the peripheral blood of systemic lupus erythematosus patients using an hMeDIP-chip WEIGUO SUI1*, QIUPEI TAN1*, MING YANG1, QIANG YAN1, HUA LIN1, MINGLIN OU1, WEN XUE1, JIEJING CHEN1, TONGXIANG ZOU1, HUANYUN JING1, LI GUO1, CUIHUI CAO1, YUFENG SUN1, ZHENZHEN CUI1 and YONG DAI2 1Guangxi Key Laboratory of Metabolic Diseases Research, Central Laboratory of Guilin 181st Hospital, Guilin, Guangxi 541002; 2Clinical Medical Research Center, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, P.R. China Received July 9, 2014; Accepted February 27, 2015 DOI: 10.3892/ijmm.2015.2149 Abstract. Systemic lupus erythematosus (SLE) is a chronic, Introduction potentially fatal systemic autoimmune disease characterized by the production of autoantibodies against a wide range Systemic lupus erythematosus (SLE) is a typical systemic auto- of self-antigens. To investigate the role of the 5-hmC DNA immune disease, involving diffuse connective tissues (1) and modification with regard to the onset of SLE, we compared is characterized by immune inflammation. SLE has a complex the levels 5-hmC between SLE patients and normal controls. pathogenesis (2), involving genetic, immunologic and envi- Whole blood was obtained from patients, and genomic DNA ronmental factors. Thus, it may result in damage to multiple was extracted. Using the hMeDIP-chip analysis and valida- tissues and organs, especially the kidneys (3). SLE arises from tion by quantitative RT-PCR (RT-qPCR), we identified the a combination of heritable and environmental influences. differentially hydroxymethylated regions that are associated Epigenetics, the study of changes in gene expression with SLE.
    [Show full text]
  • Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells
    Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts.
    [Show full text]
  • Chr21 Protein-Protein Interactions: Enrichment in Products Involved in Intellectual Disabilities, Autism and Late Onset Alzheimer Disease
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.872606; this version posted December 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease Julia Viard1,2*, Yann Loe-Mie1*, Rachel Daudin1, Malik Khelfaoui1, Christine Plancon2, Anne Boland2, Francisco Tejedor3, Richard L. Huganir4, Eunjoon Kim5, Makoto Kinoshita6, Guofa Liu7, Volker Haucke8, Thomas Moncion9, Eugene Yu10, Valérie Hindie9, Henri Bléhaut11, Clotilde Mircher12, Yann Herault13,14,15,16,17, Jean-François Deleuze2, Jean- Christophe Rain9, Michel Simonneau1, 18, 19, 20** and Aude-Marie Lepagnol- Bestel1** 1 Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France 2 Laboratoire de génomique fonctionnelle, CNG, CEA, Evry 3 Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez-Campus de San Juan 03550 San Juan (Alicante), Spain 4 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA 5 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea 6 Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan 7 Department of Biological Sciences, University of Toledo, Toledo, OH, 43606, USA 8 Leibniz Forschungsinstitut für Molekulare Pharmakologie
    [Show full text]
  • Environmental Influences on Endothelial Gene Expression
    ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community.
    [Show full text]
  • Investigating the Genetic Basis of Cisplatin-Induced Ototoxicity in Adult South African Patients
    --------------------------------------------------------------------------- Investigating the genetic basis of cisplatin-induced ototoxicity in adult South African patients --------------------------------------------------------------------------- by Timothy Francis Spracklen SPRTIM002 SUBMITTED TO THE UNIVERSITY OF CAPE TOWN In fulfilment of the requirements for the degree MSc(Med) Faculty of Health Sciences UNIVERSITY OF CAPE TOWN University18 December of Cape 2015 Town Supervisor: Prof. Rajkumar S Ramesar Co-supervisor: Ms A Alvera Vorster Division of Human Genetics, Department of Pathology, University of Cape Town 1 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town Declaration I, Timothy Spracklen, hereby declare that the work on which this dissertation/thesis is based is my original work (except where acknowledgements indicate otherwise) and that neither the whole work nor any part of it has been, is being, or is to be submitted for another degree in this or any other university. I empower the university to reproduce for the purpose of research either the whole or any portion of the contents in any manner whatsoever. Signature: Date: 18 December 2015 ' 2 Contents Abbreviations ………………………………………………………………………………….. 1 List of figures …………………………………………………………………………………... 6 List of tables ………………………………………………………………………………….... 7 Abstract ………………………………………………………………………………………… 10 1. Introduction …………………………………………………………………………………. 11 1.1 Cancer …………………………………………………………………………….. 11 1.2 Adverse drug reactions ………………………………………………………….. 12 1.3 Cisplatin …………………………………………………………………………… 12 1.3.1 Cisplatin’s mechanism of action ……………………………………………… 13 1.3.2 Adverse reactions to cisplatin therapy ……………………………………….
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Gene Expression Imputation Across Multiple Brain Regions Provides Insights Into Schizophrenia Risk
    VU Research Portal Gene expression imputation across multiple brain regions provides insights into schizophrenia risk iPSYCH-GEMS Schizophrenia Working Group; CommonMind Consortium; The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium published in Nature Genetics 2019 DOI (link to publisher) 10.1038/s41588-019-0364-4 document version Publisher's PDF, also known as Version of record document license Article 25fa Dutch Copyright Act Link to publication in VU Research Portal citation for published version (APA) iPSYCH-GEMS Schizophrenia Working Group, CommonMind Consortium, & The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium (2019). Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics, 51(4), 659–674. https://doi.org/10.1038/s41588-019-0364-4 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 ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 28.
    [Show full text]
  • Systems Analysis Implicates WAVE2&Nbsp
    JACC: BASIC TO TRANSLATIONAL SCIENCE VOL.5,NO.4,2020 ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). PRECLINICAL RESEARCH Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects a b b b Jonathan J. Edwards, MD, Andrew D. Rouillard, PHD, Nicolas F. Fernandez, PHD, Zichen Wang, PHD, b c d d Alexander Lachmann, PHD, Sunita S. Shankaran, PHD, Brent W. Bisgrove, PHD, Bradley Demarest, MS, e f g h Nahid Turan, PHD, Deepak Srivastava, MD, Daniel Bernstein, MD, John Deanfield, MD, h i j k Alessandro Giardini, MD, PHD, George Porter, MD, PHD, Richard Kim, MD, Amy E. Roberts, MD, k l m m,n Jane W. Newburger, MD, MPH, Elizabeth Goldmuntz, MD, Martina Brueckner, MD, Richard P. Lifton, MD, PHD, o,p,q r,s t d Christine E. Seidman, MD, Wendy K. Chung, MD, PHD, Martin Tristani-Firouzi, MD, H. Joseph Yost, PHD, b u,v Avi Ma’ayan, PHD, Bruce D. Gelb, MD VISUAL ABSTRACT Edwards, J.J. et al. J Am Coll Cardiol Basic Trans Science. 2020;5(4):376–86. ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2020.01.012 JACC: BASIC TO TRANSLATIONALSCIENCEVOL.5,NO.4,2020 Edwards et al. 377 APRIL 2020:376– 86 WAVE2 Complex in LVOTO HIGHLIGHTS ABBREVIATIONS AND ACRONYMS Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes.
    [Show full text]
  • Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
    Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen,
    [Show full text]
  • The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid
    The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome Annette K. Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik and Øystein Bruserud Supplementary Material S2 of S31 Table S1. Detailed information about the 68 AML patients included in the study. # of blasts Viability Proliferation Cytokine Viable cells Change in ID Gender Age Etiology FAB Cytogenetics Mutations CD34 Colonies (109/L) (%) 48 h (cpm) secretion (106) 5 weeks phenotype 1 M 42 de novo 241 M2 normal Flt3 pos 31.0 3848 low 0.24 7 yes 2 M 82 MF 12.4 M2 t(9;22) wt pos 81.6 74,686 low 1.43 969 yes 3 F 49 CML/relapse 149 M2 complex n.d. pos 26.2 3472 low 0.08 n.d. no 4 M 33 de novo 62.0 M2 normal wt pos 67.5 6206 low 0.08 6.5 no 5 M 71 relapse 91.0 M4 normal NPM1 pos 63.5 21,331 low 0.17 n.d. yes 6 M 83 de novo 109 M1 n.d. wt pos 19.1 8764 low 1.65 693 no 7 F 77 MDS 26.4 M1 normal wt pos 89.4 53,799 high 3.43 2746 no 8 M 46 de novo 26.9 M1 normal NPM1 n.d. n.d. 3472 low 1.56 n.d. no 9 M 68 MF 50.8 M4 normal D835 pos 69.4 1640 low 0.08 n.d.
    [Show full text]
  • Genome-Wide Screen of Cell-Cycle Regulators in Normal and Tumor Cells
    bioRxiv preprint doi: https://doi.org/10.1101/060350; this version posted June 23, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion Maria Sokolova1, Mikko Turunen1, Oliver Mortusewicz3, Teemu Kivioja1, Patrick Herr3, Anna Vähärautio1, Mikael Björklund1, Minna Taipale2, Thomas Helleday3 and Jussi Taipale1,2,* 1Genome-Scale Biology Program, P.O. Box 63, FI-00014 University of Helsinki, Finland. 2Science for Life laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, SE- 141 83 Stockholm, Sweden. 3Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden To identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells.
    [Show full text]