Transcriptome-Wide Analysis and Modelling of Prognostic
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Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma
Anatomy and Pathology Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma Sarah L. Lake,1 Sarah E. Coupland,1 Azzam F. G. Taktak,2 and Bertil E. Damato3 PURPOSE. To detect deletions and loss of heterozygosity of disease is fatal in 92% of patients within 2 years of diagnosis. chromosome 3 in a rare subset of fatal, disomy 3 uveal mela- Clinical and histopathologic risk factors for UM metastasis noma (UM), undetectable by fluorescence in situ hybridization include large basal tumor diameter (LBD), ciliary body involve- (FISH). ment, epithelioid cytomorphology, extracellular matrix peri- ϩ ETHODS odic acid-Schiff-positive (PAS ) loops, and high mitotic M . Multiplex ligation-dependent probe amplification 3,4 5 (MLPA) with the P027 UM assay was performed on formalin- count. Prescher et al. showed that a nonrandom genetic fixed, paraffin-embedded (FFPE) whole tumor sections from 19 change, monosomy 3, correlates strongly with metastatic death, and the correlation has since been confirmed by several disomy 3 metastasizing UMs. Whole-genome microarray analy- 3,6–10 ses using a single-nucleotide polymorphism microarray (aSNP) groups. Consequently, fluorescence in situ hybridization were performed on frozen tissue samples from four fatal dis- (FISH) detection of chromosome 3 using a centromeric probe omy 3 metastasizing UMs and three disomy 3 tumors with Ͼ5 became routine practice for UM prognostication; however, 5% years’ metastasis-free survival. to 20% of disomy 3 UM patients unexpectedly develop metas- tases.11 Attempts have therefore been made to identify the RESULTS. Two metastasizing UMs that had been classified as minimal region(s) of deletion on chromosome 3.12–15 Despite disomy 3 by FISH analysis of a small tumor sample were found these studies, little progress has been made in defining the key on MLPA analysis to show monosomy 3. -
Ankrd9 Is a Metabolically-Controlled Regulator of Impdh2 Abundance and Macro-Assembly
ANKRD9 IS A METABOLICALLY-CONTROLLED REGULATOR OF IMPDH2 ABUNDANCE AND MACRO-ASSEMBLY by Dawn Hayward A dissertation submitted to The Johns Hopkins University in conformity with the requirements of the degree of Doctor of Philosophy Baltimore, Maryland April 2019 ABSTRACT Members of a large family of Ankyrin Repeat Domains proteins (ANKRD) regulate numerous cellular processes by binding and changing properties of specific protein targets. We show that interactions with a target protein and the functional outcomes can be markedly altered by cells’ metabolic state. ANKRD9 facilitates degradation of inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in GTP biosynthesis. Under basal conditions ANKRD9 is largely segregated from the cytosolic IMPDH2 by binding to vesicles. Upon nutrient limitation, ANKRD9 loses association with vesicles and assembles with IMPDH2 into rod-like structures, in which IMPDH2 is stable. Inhibition of IMPDH2 with Ribavirin favors ANKRD9 binding to rods. The IMPDH2/ANKRD9 assembly is reversed by guanosine, which restores association of ANKRD9 with vesicles. The conserved Cys109Cys110 motif in ANKRD9 is required for the vesicles-to-rods transition as well as binding and regulation of IMPDH2. ANKRD9 knockdown increases IMPDH2 levels and prevents formation of IMPDH2 rods upon nutrient limitation. Thus, the status of guanosine pools affects the mode of ANKRD9 action towards IMPDH2. Advisor: Dr. Svetlana Lutsenko, Department of Physiology, Johns Hopkins University School of Medicine Second reader: -
An Amplified Fatty Acid-Binding Protein Gene Cluster In
cancers Review An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis Rong-Zong Liu and Roseline Godbout * Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-780-432-8901 Received: 6 November 2020; Accepted: 16 December 2020; Published: 18 December 2020 Simple Summary: Prostate cancer is the second most common cancer in men. In many cases, prostate cancer grows very slowly and remains confined to the prostate. These localized cancers can usually be cured. However, prostate cancer can also metastasize to other organs of the body, which often results in death of the patient. We found that a cluster of genes involved in accumulation and utilization of fats exists in multiple copies and is expressed at much higher levels in metastatic prostate cancer compared to localized disease. These genes, called fatty acid-binding protein (or FABP) genes, individually and collectively, promote properties associated with prostate cancer metastasis. We propose that levels of these FABP genes may serve as an indicator of prostate cancer aggressiveness, and that inhibiting the action of FABP genes may provide a new approach to prevent and/or treat metastatic prostate cancer. Abstract: Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed. -
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. -
Structural Basis for DEAH-Helicase Activation by G-Patch Proteins
Structural basis for DEAH-helicase activation by G-patch proteins Michael K. Studera, Lazar Ivanovica, Marco E. Webera, Sabrina Martia, and Stefanie Jonasa,1 aInstitute of Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology (ETH) Zürich, 8093 Zürich, Switzerland Edited by Joseph D. Puglisi, Stanford University School of Medicine, Stanford, CA, and approved February 21, 2020 (received for review August 12, 2019) RNA helicases of the DEAH/RHA family are involved in many essential RNA bases are stacked in the RNA binding channel between a long cellular processes, such as splicing or ribosome biogenesis, where β-hairpin in RecA2 (β14 to β15 in hsDHX15/scPrp43; SI Appendix, they remodel large RNA–protein complexes to facilitate transitions Fig. S1) and a conserved loop in RecA1 (termed “Hook-turn”). to the next intermediate. DEAH helicases couple adenosine tri- This means that during progression into the open state, the phosphate (ATP) hydrolysis to conformational changes of their β-hairpin and two other RNA-binding patches in RecA2 (termed catalytic core. This movement results in translocation along RNA, “Hook-loop” and “motif V”; SI Appendix, Fig. S1) have to shift 1 which is held in place by auxiliary C-terminal domains. The activity nucleotide (nt) toward the 5′ end of the RNA. Thus, when the of DEAH proteins is strongly enhanced by the large and diverse RecA domains close back up, at the start of the next hydrolysis class of G-patch activators. Despite their central roles in RNA me- cycle, the RNA is pushed by 1 nt through the RNA channel. -
(12) United States Patent (10) Patent No.: US 7,592,444 B2 Khvorova Et Al
USOO7592444B2 (12) United States Patent (10) Patent No.: US 7,592,444 B2 KhVOrOVa et al. (45) Date of Patent: Sep. 22, 2009 (54) SIRNA TARGETING MYELOID CELL 2003/0228597 A1 12/2003 COWSert LEUKEMIA SEQUENCE 1 2004/OO29275 A1 2/2004 Brown et al. 2004.00541.55 A1 3, 2004 Woolf (75) Inventors: Anastasia Khvorova, Boulder, CO 2004-0063654. A 42004 Davis et al. (US); Angela Reynolds, Conifer, CO S.S. A. 3. Singhofer (US);O O Devin Leake, Denver, CO (US); 2004/O180357 A1 9, 2004 eich William Marshall, Boulder, CO (US); 2004/O192629 A1 9, 2004 Xu et al. Stephen Scaringe, Lafayette, CO (US); 2004/0204380 A1 10, 2004 Ackerman Steven Read, Boulder, CO (US) 2004/0219671 A1 1 1/2004 McSwiggen 2004/024.8296 A1 12/2004 Beresford (73) Assignee: Dharmacon, Inc., Lafayette, CO (US) 2004/0248299 A1 12/2004 Jayasena 2004/0259247 A1 12, 2004 TuSchlet al. (*) Notice: Subject to any disclaimer, the term of this 2005/0048529 A1 3/2005 McSwiggen patent is extended or adjusted under 35 2005/0107328 A1 5/2005 Wyatt U.S.C. 154(b) by 0 days. 2005. O130181 A1 6/2005 McSwiggen 2005/0176O25 A1 8/2005 McSwiggen (21) Appl. No.: 12/378,164 2005, 0181382 A1 8, 2005 Zamore 2005, 0186586 A1 8, 2005 Zamore 2005/0227935 A1 10/2005 McSwiggen (22) Filed: Feb. 11, 2009 2005/0239731 A1 10/2005 McSwiggen 2005.0245475 A1 11/2005 Khvorova (65) Prior Publication Data 2006/0286575 A1 12/2006 Farrell US 2009/O1637O2A1 Jun. 25, 2009 2007/0031844 A1 2/2007 Khvorova 2007,0254.850 A1 11/2007 Lieberman Related U.S. -
RBM5/LUCA-15 Tumour Suppression by Control of Apoptosis and the Cell
Review Article TheScientificWorldJOURNAL (2002) 2, 1885–1890 ISSN 1537-744X; DOI 10.1100/tsw.2002.859 RBM5/LUCA-15 —Tumour Suppression by Control of Apoptosis and the Cell Cycle? Mirna Mourtada-Maarabouni1 and Gwyn T. Williams2 School of Life Sciences, Keele University, Keele, Staffs, ST5 5BG, U.K. 1 2 TEL: 44 1782 583679, FAX 44 1782 583516; TEL: 44 1782 583032, FAX: 44 1782 583516 E-mail: [email protected]; [email protected] Received March 19, 2002; Revised May 17, 2002; Accepted May 17, 2002; Published July 4, 2002 The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. The LUCA-15 gene locus encodes at least four alternatively spliced transcripts, which have been shown to function as regulators of apoptosis, a fact that may have a major significance in tumour regulation. This review highlights evidence that implicates the LUCA-15 locus in the control of apoptosis and cell proliferation, and reports observations that significantly strengthen the case for tumour suppressor activity by this gene. KEY WORDS: T-lymphocytes, LUCA-15, RNA-binding proteins, cell death, cell proliferation DOMAINS: cell death, cell cycle, oncology, gene regulation INTRODUCTION The molecular control of cancer is complex. Cancer genes are involved in the dysregulation of a whole range of normal cellular systemic processes including cell proliferation[1], cell-cell communication[2], DNA repair[3], chromosome stability[4], tumour invasion, motility and metastasis[5,6], apoptosis[7], and others. Despite impressive progress in recent years in understanding the molecular basis of cancer, many crucial genes remain to be identified. -
Análise Integrativa De Perfis Transcricionais De Pacientes Com
UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 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 Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. -
Methylglyoxal Down-Regulates the Expression of Cell Cycle Associated
www.nature.com/scientificreports OPEN Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 Received: 8 May 2018 Accepted: 12 December 2018 pathway in human umbilical vein Published: xx xx xxxx endothelial cells Jana D. Braun1, Diego O. Pastene1, Annette Breedijk1, Angelica Rodriguez1, Björn B. Hofmann1, Carsten Sticht2, Elke von Ochsenstein3, Heike Allgayer3, Jacob van den Born4, Stephan Bakker4, Sibylle J. Hauske1, Bernhard K. Krämer1, Benito A. Yard1 & Thomas Albrecht1 Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the infuence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade infammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an infammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this afected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations signifcantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identifed six signifcantly enriched pathways of which the p53 pathway was the most afected. No signifcant enrichment of infammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine signifcantly counteracted MGO-mediated changes in a subset of diferentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. -
Sleeping Beauty Transposon Mutagenesis Identifies Genes That
Sleeping Beauty transposon mutagenesis identifies PNAS PLUS genes that cooperate with mutant Smad4 in gastric cancer development Haruna Takedaa,b, Alistair G. Rustc,d, Jerrold M. Warda, Christopher Chin Kuan Yewa, Nancy A. Jenkinsa,e, and Neal G. Copelanda,e,1 aDivision of Genomics and Genetics, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; bDepartment of Pathology, School of Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan; cExperimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom; dTumour Profiling Unit, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, United Kingdom; and eCancer Research Program, Houston Methodist Research Institute, Houston, TX 77030 Contributed by Neal G. Copeland, February 27, 2016 (sent for review October 15, 2015; reviewed by Yoshiaki Ito and David A. Largaespada) Mutations in SMAD4 predispose to the development of gastroin- animal models that mimic human GC, researchers have infected testinal cancer, which is the third leading cause of cancer-related mice with H. pylori and then, treated them with carcinogens. They deaths. To identify genes driving gastric cancer (GC) development, have also used genetic engineering to develop a variety of trans- we performed a Sleeping Beauty (SB) transposon mutagenesis genic and KO mouse models of GC (10). Smad4 KO mice are one + − screen in the stomach of Smad4 / mutant mice. This screen iden- GC model that has been of particular interest to us (11, 12). tified 59 candidate GC trunk drivers and a much larger number of Heterozygous Smad4 KO mice develop polyps in the pyloric re- candidate GC progression genes. -
Supplemental Information Figure S1. Genome-Wide Alternative Splicing
Supplemental information Figure S1. Genome-wide alternative splicing events affected by inducible expression SRSF3 in mouse MEF3T3 cells. To examine the effects of SRSF3 (SRp20) on genome-wide RNA splicing in mouse cells, we utilized Exonhit SpliceArray to compare genome-wide changes of RNA splicing and transcription in MEF3T3 mouse fibroblasts with or without ectopically inducible expression of SRp20. (A–C) Clustered heat maps for the top events regulated by SRSF3 identified by ExonHit splice arrays. SRSF3-targeted genes in three experimental repeats consist of 65 evidenced splicing events (A), 74 novel splicing events (B) and 11 genes with expression changes (C), with a threshold of ≥2-fold changes (p<0.01) in log2 as determined by a B/E method and FDR cutoff of 0.1 for gene expression change and 0.2 for splicing alternation. Individual gene names and event ID are indicated on the right. Event ID specifies individual splicing events being detailed in Supplementary Table S1-S3. MEF3T3 cells with an empty vector transfection were included as vector controls. Color key scales in log2 values are indicated at the bottom of each panel. The full list of B/E ratio analysis result is available at NCBI GEO (http://www.ncbi.nlm.nih.gov/geo/) (accession number GSE60147). Figure S2. Isoform profiling of mouse Ilf3 and human ILF3. (A) Diagrams of RNA isoforms of mouse Ilf3. Mouse Ilf3 consists of 22 exons and 21 introns, which produces 6 spliced isoforms of mRNAs by alternative splicing as illustrated. (B) Diagrams of splice isoforms of human ILF3. Human ILF3 gene consists of 21 exons (boxes) and 20 introns (lines between boxes), which produce 8 splice isoforms of mRNAs by alternative splicing as depicted. -
Human Brain Organoids Reveal Accelerated Development of Cortical Neuron Classes As a Shared Feature of Autism Risk Genes
bioRxiv preprint doi: https://doi.org/10.1101/2020.11.10.376509; this version posted November 12, 2020. 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. Human brain organoids reveal accelerated development of cortical neuron classes as a shared feature of autism risk genes Bruna Paulsen1,2,†, Silvia Velasco1,2,†,#, Amanda J. Kedaigle1,2,3,†, Martina Pigoni1,2,†, Giorgia Quadrato4,5 Anthony Deo2,6,7,8, Xian Adiconis2,3, Ana Uzquiano1,2, Kwanho Kim1,2,3, Sean K. Simmons2,3, Kalliopi Tsafou2, Alex Albanese9, Rafaela Sartore1,2, Catherine Abbate1,2, Ashley Tucewicz1,2, Samantha Smith1,2, Kwanghun Chung9,10,11,12, Kasper Lage2,13, Aviv Regev3,14, Joshua Z. Levin2,3, Paola Arlotta1,2,# † These authors contributed equally to the work # Correspondence should be addressed to [email protected] and [email protected] 1 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA 2 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 3 Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 4 Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; 5 Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at the University of Southern California, Los Angeles, CA 90033, USA. 6 Department of Psychiatry,