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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. -
UNIVERSITY of CALIFORNIA, SAN DIEGO Towards an Understanding of Inflammation in Macrophages a Dissertation Submitted in Partial
UNIVERSITY OF CALIFORNIA, SAN DIEGO Towards an Understanding of Inflammation in Macrophages A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Dawn Xiaobin Zhang Committee in charge: Professor Christopher L. Glass, Chair Professor Jack Bui Professor Ronald M. Evans Professor Richard L. Gallo Professor Joseph L. Witztum 2014 Copyright Dawn Xiaobin Zhang, 2014 All rights reserved. This Dissertation of Dawn Xiaobin Zhang is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2014 iii DEDICATION To my family and the love of my life, Matthew. iv EPIGRAPH How often have I said to you that when you have eliminated the impossible, whatever remains, however improbable, must be the truth? -Sherlock Holmes, From The Sign of the Four, Sir Arthur Conan Doyle v TABLE OF CONTENTS Signature Page ……………………………………………………………….. iii Dedication ……………………………………………………….…………….. iv Epigraph ……………………………………………………………………….. v Table of Contents ………………………………………………………….….. vi List of Figures ………………………………………………………….………. viii List of Tables ………………………………………………………….…….…. x Acknowledgements …………………………………….…………………..…. xi Vita …………………………………….……………………………………..…. xiii Abstract of the Dissertation ………………………………..…………………. xv Chapter I: Introduction: Towards an Understanding of Cell-Specific Function of Signal-Dependent Transcription Factors ……....…....…... 1 A. Abstract ……....…....………………………………...…………….. 2 B. Introduction -
Associated 16P11.2 Deletion in Drosophila Melanogaster
ARTICLE DOI: 10.1038/s41467-018-04882-6 OPEN Pervasive genetic interactions modulate neurodevelopmental defects of the autism- associated 16p11.2 deletion in Drosophila melanogaster Janani Iyer1, Mayanglambam Dhruba Singh1, Matthew Jensen1,2, Payal Patel 1, Lucilla Pizzo1, Emily Huber1, Haley Koerselman3, Alexis T. Weiner 1, Paola Lepanto4, Komal Vadodaria1, Alexis Kubina1, Qingyu Wang 1,2, Abigail Talbert1, Sneha Yennawar1, Jose Badano 4, J. Robert Manak3,5, Melissa M. Rolls1, Arjun Krishnan6,7 & 1234567890():,; Santhosh Girirajan 1,2,8 As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of indi- vidual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interac- tions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes. 1 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. 2 Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. -
HHS Public Access Author Manuscript
HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Immunol Author Manuscript. Author manuscript; Author Manuscript available in PMC 2009 May 01. Published in final edited form as: Nat Immunol. 2008 November ; 9(11): 1307–1315. doi:10.1038/ni.1662. The actin regulator coronin-1A is mutated in a thymic egress deficient mouse strain and in a T−B+NK+ SCID patient Lawrence R. Shiow1,2,3, David W. Roadcap5, Kenneth Paris7, Susan R. Watson2, Irina L. Grigorova1,2, Tonya Lebet2,4, Jinping An1,2, Ying Xu1,2, Craig N. Jenne1,2, Niko Föger8, Ricardo U. Sorensen7, Christopher C. Goodnow6, James E. Bear5, Jennifer M. Puck3,4, and Jason G. Cyster1,2,3 1 Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 2 Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 3 Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 4 Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, CA 5 Lineberger Comprehensive Cancer Center and Department of Cell and Developmental Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 6 John Curtin School of Medical Research, The Australian National University, Canberra, Australia 7 Department of Pediatrics, Louisiana State University Health Sciences Center and Children’s Hospital, New Orleans, LA 8 Department of Immunology and Cell Biology, Leibniz Center for Medicine and Biosciences, Borstel, Germany Abstract Mice carrying the recessive peripheral T cell deficiency (Ptcd) locus have a block in thymic egress but the mechanism responsible is undefined. -
Integrating Protein Copy Numbers with Interaction Networks to Quantify Stoichiometry in Mammalian Endocytosis
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. 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-ND 4.0 International license. Integrating protein copy numbers with interaction networks to quantify stoichiometry in mammalian endocytosis Daisy Duan1, Meretta Hanson1, David O. Holland2, Margaret E Johnson1* 1TC Jenkins Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218. 2NIH, Bethesda, MD, 20892. *Corresponding Author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. 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-ND 4.0 International license. Abstract Proteins that drive processes like clathrin-mediated endocytosis (CME) are expressed at various copy numbers within a cell, from hundreds (e.g. auxilin) to millions (e.g. clathrin). Between cell types with identical genomes, copy numbers further vary significantly both in absolute and relative abundance. These variations contain essential information about each protein’s function, but how significant are these variations and how can they be quantified to infer useful functional behavior? Here, we address this by quantifying the stoichiometry of proteins involved in the CME network. We find robust trends across three cell types in proteins that are sub- vs super-stoichiometric in terms of protein function, network topology (e.g. -
Open Full Page
Published OnlineFirst February 10, 2017; DOI: 10.1158/2159-8290.CD-16-1045 RESEARCH ARTICLE Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer Hannah Carter 1 , 2 , 3 , 4 , Rachel Marty 5 , Matan Hofree 6 , Andrew M. Gross 5 , James Jensen 5 , Kathleen M. Fisch1,2,3,7 , Xingyu Wu 2 , Christopher DeBoever 5 , Eric L. Van Nostrand 4,8 , Yan Song 4,8 , Emily Wheeler 4,8 , Jason F. Kreisberg 1,3 , Scott M. Lippman 2 , Gene W. Yeo 4,8 , J. Silvio Gutkind 2 , 3 , and Trey Ideker 1 , 2 , 3 , 4 , 5,6 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 10, 2017; DOI: 10.1158/2159-8290.CD-16-1045 ABSTRACT Recent studies have characterized the extensive somatic alterations that arise dur- ing cancer. However, the somatic evolution of a tumor may be signifi cantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5,954 tumors to reveal and systematically validate 412 genetic interactions between germline polymorphisms and major somatic events, including tumor formation in specifi c tissues and alteration of specifi c cancer genes. Among germline–somatic interactions, we found germline variants in RBFOX1 that increased incidence of SF3B1 somatic mutation by 8-fold via functional alterations in RNA splicing. Similarly, 19p13.3 variants were associated with a 4-fold increased likelihood of somatic mutations in PTEN. In support of this associ- ation, we found that PTEN knockdown sensitizes the MTOR pathway to high expression of the 19p13.3 gene GNA11 . -
Prediction of Candidate Primary Immunodeficiency Disease Genes
DNA RESEARCH 16, 345–351, (2009) doi:10.1093/dnares/dsp019 Prediction of Candidate Primary Immunodeficiency Disease Genes Using a Support Vector Machine Learning Approach SHIVAKUMAR Keerthikumar1,2,3,SAHELY Bhadra4,KUMARAN Kandasamy1,2,5,RAJESH Raju1,2,3, Y.L. Ramachandra2,CHIRANJIB Bhattacharyya4,KOHSUKE Imai8,OSAMU Ohara6,7, SUJATHA Mohan1,3, and AKHILESH Pandey1,5,* Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India1; Department of Biotechnology and Bioinformatics, Kuvempu University, Jnanasahyadri, Shimoga 577 451, India2; Research Unit for Immunoinformatics, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa 230- 0045, Japan3; Department of Computer Science and Automation, Indian Institute of Science, Bangalore 560 012, India4; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, BRB Room 527, Baltimore, MD 21205, USA5; Laboratory for Immunogenomics, Research Center for Allergy and Immunology, RIKEN, Yokohama Institute, Kanagawa 230-0045, Japan6; Department of Human Genome Technology, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan7 and Department of Medical Informatics, National Defense Medical College, Saitama 359-8513, Japan8 (Received 23 July 2009; accepted 5 September 2009; published online 3 October 2009) Abstract Screening and early identification of primary immunodeficiency disease (PID) genes is a major chal- lenge for physicians. Many resources have catalogued molecular alterations in known PID genes along with their associated clinical and immunological phenotypes. However, these resources do not assist in identifying candidate PID genes. We have recently developed a platform designated Resource of Asian PDIs, which hosts information pertaining to molecular alterations, protein–protein interaction networks, mouse studies and microarray gene expression profiling of all known PID genes. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
Single-Cell Transcriptomes Reveal a Complex Cellular Landscape in the Middle Ear and Differential Capacities for Acute Response to Infection
fgene-11-00358 April 9, 2020 Time: 15:55 # 1 ORIGINAL RESEARCH published: 15 April 2020 doi: 10.3389/fgene.2020.00358 Single-Cell Transcriptomes Reveal a Complex Cellular Landscape in the Middle Ear and Differential Capacities for Acute Response to Infection Allen F. Ryan1*, Chanond A. Nasamran2, Kwang Pak1, Clara Draf1, Kathleen M. Fisch2, Nicholas Webster3 and Arwa Kurabi1 1 Departments of Surgery/Otolaryngology, UC San Diego School of Medicine, VA Medical Center, La Jolla, CA, United States, 2 Medicine/Center for Computational Biology & Bioinformatics, UC San Diego School of Medicine, VA Medical Center, La Jolla, CA, United States, 3 Medicine/Endocrinology, UC San Diego School of Medicine, VA Medical Center, La Jolla, CA, United States Single-cell transcriptomics was used to profile cells of the normal murine middle ear. Clustering analysis of 6770 transcriptomes identified 17 cell clusters corresponding to distinct cell types: five epithelial, three stromal, three lymphocyte, two monocyte, Edited by: two endothelial, one pericyte and one melanocyte cluster. Within some clusters, Amélie Bonnefond, Institut National de la Santé et de la cell subtypes were identified. While many corresponded to those cell types known Recherche Médicale (INSERM), from prior studies, several novel types or subtypes were noted. The results indicate France unexpected cellular diversity within the resting middle ear mucosa. The resolution of Reviewed by: Fabien Delahaye, uncomplicated, acute, otitis media is too rapid for cognate immunity to play a major Institut Pasteur de Lille, France role. Thus innate immunity is likely responsible for normal recovery from middle ear Nelson L. S. Tang, infection. The need for rapid response to pathogens suggests that innate immune The Chinese University of Hong Kong, China genes may be constitutively expressed by middle ear cells. -
Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/). -
Diagnostic Interpretation of Genetic Studies in Patients with Primary
AAAAI Work Group Report Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology Ivan K. Chinn, MD,a,b Alice Y. Chan, MD, PhD,c Karin Chen, MD,d Janet Chou, MD,e,f Morna J. Dorsey, MD, MMSc,c Joud Hajjar, MD, MS,a,b Artemio M. Jongco III, MPH, MD, PhD,g,h,i Michael D. Keller, MD,j Lisa J. Kobrynski, MD, MPH,k Attila Kumanovics, MD,l Monica G. Lawrence, MD,m Jennifer W. Leiding, MD,n,o,p Patricia L. Lugar, MD,q Jordan S. Orange, MD, PhD,r,s Kiran Patel, MD,k Craig D. Platt, MD, PhD,e,f Jennifer M. Puck, MD,c Nikita Raje, MD,t,u Neil Romberg, MD,v,w Maria A. Slack, MD,x,y Kathleen E. Sullivan, MD, PhD,v,w Teresa K. Tarrant, MD,z Troy R. Torgerson, MD, PhD,aa,bb and Jolan E. Walter, MD, PhDn,o,cc Houston, Tex; San Francisco, Calif; Salt Lake City, Utah; Boston, Mass; Great Neck and Rochester, NY; Washington, DC; Atlanta, Ga; Rochester, Minn; Charlottesville, Va; St Petersburg, Fla; Durham, NC; Kansas City, Mo; Philadelphia, Pa; and Seattle, Wash AAAAI Position Statements,Work Group Reports, and Systematic Reviews are not to be considered to reflect current AAAAI standards or policy after five years from the date of publication. The statement below is not to be construed as dictating an exclusive course of action nor is it intended to replace the medical judgment of healthcare professionals. -
Ernas and Superenhancer Lncrnas Are Functional in Human Prostate Cancer
Hindawi Disease Markers Volume 2020, Article ID 8847986, 17 pages https://doi.org/10.1155/2020/8847986 Research Article eRNAs and Superenhancer lncRNAs Are Functional in Human Prostate Cancer Xiaona Zhang,1,2,3 Panpan Pang,2,3,4 Min Jiang,1,2,3 Qunfa Cao,2,3 Huili Li,2,3 Yi Xu,5 Yao Li ,4 Xue Chen ,1 and Junsong Han 2,3 1Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China 2National Engineering Center for Biochip at Shanghai, Shanghai, China 3Shanghai Biochip Corporation, Shanghai, China 4Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, China 5Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Chinese Medicine, Shanghai, China Correspondence should be addressed to Yao Li; [email protected], Xue Chen; [email protected], and Junsong Han; [email protected] Received 23 June 2020; Revised 27 July 2020; Accepted 14 August 2020; Published 24 September 2020 Academic Editor: Mingjun Shi Copyright © 2020 Xiaona Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. lncRNAs (long noncoding RNAs) play a significant role in the occurrence and development of PCa. eRNAs (enhancer RNAs) and SE-lncRNAs (superenhancer lncRNAs) are important elements of lncRNAs, but the role of eRNAs and SE-lncRNAs in PCa remains largely unclear. In this work, we identified 681 eRNAs and 292 SE-lncRNAs that were expressed differentially in PCa using a microarray.