Deletion of the RAG2 C Terminus Leads to Impaired Lymphoid Development in Mice
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
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. -
In Silico Analysis of Single Nucleotide Polymorphism (Snps) in Human RAG1 and RAG2 Genes of Severe Combined Immunodeficiency
Central JSM Bioinformatics, Genomics and Proteomics Bringing Excellence in Open Access Research Article *Corresponding author Mona Shams Aldeen S. Ali, Department of Applied Bioinformatics, Africa City of Technology, Khartoum, In silico Analysis of Single Sudan, Tel: 249121784688; Email: Submitted: 26 May 2016 Nucleotide Polymorphism Accepted: 17 June 2016 Published: 27 June 2016 (SNPs) in Human RAG1 and Copyright © 2016 Ali et al. RAG2 Genes of Severe OPEN ACCESS Keywords Combined Immunodeficiency • Severe combined immunodeficiency • Primary immunodeficiency Mona Shams Aldeen S. Ali1,2*, Tomador Siddig MZ1,2, Rehab A. • T lymphocytes Elhadi1,2, Muhammad Rahama Yousof2, Siddig Eltyeb Yousif • Recombinase activating genes • non synonymous Single Nucleotide Polymorphisms Abdallah1, Maiada Mohamed Yousif Ahmed2, Nosiba Yahia Mohamed Hassen1, Sulum Omer Masoud Mohamed1, Marwa Mohamed Osman2, and Mohamed A. Hassan2 1Department of Rheumatology, Omdurman Teaching Hospital, Sudan 2Department of Applied Bioinformatics, Africa City of Technology, Sudan Abstract Severe combined immunodeficiency is an inherited Primary immunodeficiency PID, which is characterized by the absence or dysfunction of T lymphocytes. Defects in RAG1 and RAG2 are known to cause a T-B-NK+ form of SCID. Recombinase activating genes RAG1 and RAG2 (OMIM 179615,179616 respectively) are expressed exclusively in lymphocytes and mediate the creation of double-strand. DNA breaks at the sites of recombination and in signal sequences during T− and B− cell receptor gene rearrangement. This study was focused on the effect of nonsynonymous single nucleotide polymorphisms in the function and structure of RAG1& RAG2 genes using In silico analysis. Only nsSNPs and 3’UTR SNPs were selected for computational analysis. Predictions of deleterious nsSNPs were performed by bioinformatics software. -
Rag2 Targeted Mutation Mice from Taconic
Rag2 Targeted Mutation Mice from Taconic In vivo Immunology Model for Drug Discovery and Toxicology The Taconic Rag2 Targeted Mutation Mouse Scientific Profile of the Rag2 Targeted Mutation Mouse1, 2 • Lacks mature T and B lymphocytes due to The Taconic Rag2 Targeted Mutation Mice an inability to initiate V(D)J rearrang-ement. carry a germline mutation in which a large Otherwise, the mouse exhibits apparently portion of the Rag2 coding region is deleted. normal hematopoiesis. Mice homozygous for the mutation are observed Potential Applications of the Rag2 to lack mature T and B lymphocytes. Analysis Targeted Mutation Mouse of these mice indicate that the Rag2 defect blocks T cell and B cell differentiation earlier • Evaluate function of lymphocyte specific and/or more completely than the scid defect. genes in immune cell differentiation (Figure 1). • Reconstitute with human hematopoietic Homozygous mutant mice were found to appear cells for research in AIDS and other immune normal except for immunological defects. cell disorders. Spleens, thymuses, and lymph nodes were small • Model human hematopoiesis for studying and hypoplastic. No detectable alterations were experimental therapeutics or developing observed in other tissues tested. vaccines. • Research the immune system's effect on Mice heterozygous for the mutation were found tumorigenesis and metastasis. to be normal compared with their wild type • Investigate somatic cell therapy in vivo. littermates. • Explore the genetics of autoimmmune or infectious diseases. Figure 1: RAG2 deficient blastocyst complementation assay. Chen, J., Lansford, R., Stewart, V., Young, F., Alt, F. Proceedings of the National Academy of Science 90, 4528-4532. 1993. (Diagram courtesy of Dr. -
Autoaggressive T Cells in the Periphery RAG2
Cutting Edge: CD40-Induced Expression of Recombination Activating Gene (RAG) 1 and RAG2: A Mechanism for the Generation of Autoaggressive T Cells in the Periphery This information is current as of September 25, 2021. Gisela M. Vaitaitis, Michelle Poulin, Richard J. Sanderson, Kathryn Haskins and David H. Wagner, Jr. J Immunol 2003; 170:3455-3459; ; doi: 10.4049/jimmunol.170.7.3455 http://www.jimmunol.org/content/170/7/3455 Downloaded from References This article cites 24 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/170/7/3455.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: CD40-Induced Expression of Recombination Activating Gene (RAG) 1 and RAG2: A Mechanism for the Generation of Autoaggressive T Cells in the Periphery1 Gisela M. -
Regulating Antigen-Receptor Gene Assembly
REVIEWS REGULATING ANTIGEN-RECEPTOR GENE ASSEMBLY Mark S. Schlissel The genes encoding antigen receptors are unique because of their high diversity and their assembly in developing lymphocytes from gene segments through a series of site-specific DNA recombination reactions known as V(D)J rearrangement. This review focuses on our understanding of how recombination of immunoglobulin and T-cell receptor gene segments is tightly regulated despite being catalysed by a common lymphoid recombinase, which recognizes a widely distributed conserved recombination signal sequence. Probable mechanisms involve precise expression of the lymphoid-restricted recombination-activating genes RAG1 and RAG2, and developmentally regulated epigenetic alterations in template accessibility, which are targeted by transcriptional regulatory elements and involve chromatin-modifying enzymes. RECOMBINATION SIGNAL It has been nearly 25 years since Tonegawa and col- V(D)J recombination: levels of regulation 1 SEQUENCES leagues shattered one of the basic assumptions of V(D)J recombination has three types of regulation — (RSSs). Short, conserved DNA molecular biology, the inviolate structure of the lineage specificity, order within a lineage and allelic sequences that flank all genome, and in so doing solved a fundamental puzzle exclusion. Transcriptional regulation limits the expres- rearranging gene segments and serve as the recognition elements in immunology — the generation of antigen-receptor sion of RAG proteins to the progenitor stages of B- for the recombinase machinery. -
Collaboration of RAG2 with RAG1-Like Proteins During the Evolution of V(D)J Recombination
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination Lina Marcela Carmona,1 Sebastian D. Fugmann,2,3 and David G. Schatz1,4 1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA; 2Department of Biomedical Sciences, Chang Gung University, Tao-Yuan City 33302, Taiwan; 3Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan City 33302, Taiwan; 4Howard Hughes Medical Institute, New Haven, Connecticut 06511, USA The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate V(D)J recombination, the process that assembles the B- and T-lymphocyte antigen receptor genes of jawed vertebrates. RAG1 and RAG2 are thought to have arisen from a transposable element, but the origins of this element are not understood. We show that two ancestral RAG1 proteins, Transib transposase and purple sea urchin RAG1-like, have a latent ability to initiate V(D)J recombination when coexpressed with RAG2 and that in vitro transposition by Transib transposase is stimulated by RAG2. Conversely, we report low levels of V(D)J recombination by RAG1 in the absence of RAG2. Recombination by RAG1 alone differs from canonical V(D)J recombination in having lost the requirement for asymmetric DNA substrates, implicating RAG2 in the origins of the “12/23 rule,” a fundamental regulatory feature of the reaction. We propose that evolution of RAG1/RAG2 began with a Transib transposon whose intrinsic recombination activity was enhanced by capture of an ancestral RAG2, allowing for the development of adaptive immunity. -
Genome-Wide Analysis Identifies Rag1 and Rag2 As Novel Notch1
fcell-09-703338 July 7, 2021 Time: 18:5 # 1 ORIGINAL RESEARCH published: 12 July 2021 doi: 10.3389/fcell.2021.703338 Genome-Wide Analysis Identifies Rag1 and Rag2 as Novel Notch1 Transcriptional Targets in Thymocytes Yang Dong1,2†, Hao Guo1,2†, Donghai Wang2, Rongfu Tu2, Guoliang Qing2* and Hudan Liu1,2* 1 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China, 2 Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China Recombination activating genes 1 (Rag1) and Rag2 are expressed in immature lymphocytes and essential for generating the vast repertoire of antigen receptors. Yet, the mechanisms governing the transcription of Rag1 and Rag2 remain to be Edited by: Binghui Li, fully determined, particularly in thymocytes. Combining cDNA microarray and ChIP- Capital Medical University, China seq analysis, we identify Rag1 and Rag2 as novel Notch1 transcriptional targets in Reviewed by: acute T-cell lymphoblastic leukemia (T-ALL) cells. We further demonstrate that Notch1 Bo Li, Sun Yat-sen University, China transcriptional complexes directly bind the Rag1 and Rag2 locus in not only T-ALL Peng Li, but also primary double negative (DN) T-cell progenitors. Specifically, dimeric Notch1 Guangzhou Institutes of Biomedicine transcriptional complexes activate Rag1 and Rag2 through a novel cis-element bearing and Health, Chinese Academy of Sciences (CAS), China a sequence-paired site (SPS). In T-ALL and DN cells, dimerization-defective Notch1 *Correspondence: causes compromised Rag1 and Rag2 expression; conversely, dimerization-competent Guoliang Qing Notch1 achieves optimal upregulation of both. Collectively, these results reveal Notch1 [email protected] Hudan Liu dimerization-mediated transcription as one of the mechanisms for activating Rag1 and [email protected] Rag2 expression in both primary and transformed thymocytes. -
Chapter 5 Genetic Models
Chapter 5 1 2 Organization and Expression of Immunoglobulin Genes 3 4 5 6 Genetic Models Models to Explain Antibody Diversity 1) The Germ Line Theory : “genome posses • How to account for : the large repertoire of antibody genes to – 1) Vast diversity of antibody specificities account for all the antibody diversity” – 2) Presence of Variable regions at the amino end of Heavy and Light chains, and a 2) The Somatic Variation Theory : “genome Constant region at the carboxyl end posses a relatively small number of – 3) Existence of isotypes (different Heavy antibody genes and diversity is generated by chains) with same antigenic specificity mutation and recombination of these genes during somatic development” The two-gene model : Tonegawa (1976): Immunoglobulin gene rearrangement • Developed by Dreyer and Bennet in 1965 • Two separate genes code for the Heavy and Light chains. One codes for the V region and the other for the C region • These genes come together during at the DNA level to form a continuous message • There are thousands of V genes in germ - J Probe - Digested fragments line but only one gene for the C region 1 Three genetic loci encode immunoglobulin molecules: - Two loci encoding the light chains Multigene Families - kappa locus - lambda locus • Light Chains : V, J and C gene segments. - One locus encoding the heavy chain • Lambda : Humans (30V, 4J and 7C genes) These three loci are located on different chromosomes. • Kappa : Humans (40V, 5J and 1C genes) • Heavy Chains : V, D, J and C gene segments • Heavy Chains : Humans (50V, 25D, 6J and 8 C genes) The loci encoding immunoglobulins have a unique structure. -
RAG2 Gene Recombination Activating 2
RAG2 gene recombination activating 2 Normal Function The RAG2 gene provides instructions for making a member of a group of proteins called the RAG complex. This complex is active in immune system cells (lymphocytes) called B cells and T cells. These cells have special proteins on their surface that recognize foreign invaders and help protect the body from infection. These proteins need to be diverse to be able to recognize a wide variety of substances. The genes from which these proteins are made contain segments known as variable (V), diversity (D), and joining (J) segments. During protein production within lymphocytes, these gene segments are rearranged in different combinations to increase variability of the resulting proteins. The RAG complex is involved in this process, which is known as V(D)J recombination. During V(D)J recombination, the RAG complex attaches (binds) to a section of DNA called a recombination signal sequence (RSS), which is next to a V, D, or J segment. The RAG complex makes small cuts in the DNA between the segment and the RSS so the segment can be separated and moved to a different area in the gene. This process of DNA rearrangement within B cells and T cells is repeated multiple times in different areas so that the V, D, and J segments are arranged in various combinations. The variety of proteins produced throughout life following V(D)J recombination provides greater recognition of foreign invaders and allows the body to fight infection efficiently. Health Conditions Related to Genetic Changes Omenn syndrome More than 20 mutations in the RAG2 gene have been found to cause an immune system disorder called Omenn syndrome. -
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. -
Immunology: Improving on Nature Review in the Twenty-First Century
CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell, Vol. 100, 129±138, January 7, 2000, Copyright 2000 by Cell Press Immunology: Improving on Nature Review in the Twenty-First Century Abul K. Abbas* and Charles A. Janeway Jr.² notion at the time, one that challenged existing concepts *Department of Pathology of how proteins conformed to the shapes of other inter- University of California San Francisco School acting proteins. Nevertheless, the clonal selection the- of Medicine ory became the foundation for our understanding of the San Francisco, California 94123 specificity and development of immune responses. The ² Section of Immunobiology molecular understanding of how the diverse repertoire Yale University School of Medicine of antigen receptors is generated came with the studies New Haven, Connecticut 06520 of Susumu Tonegawa in the 1970s (Tonegawa et al., 1977). Based on this work, and its many subsequent refinements, it is now known that the antigen receptors Introduction of B and T lymphocytes are encoded by genes that are Immunology is the study of the body's defenses against produced by somatic recombination of gene segments infection. The birth of immunology as an experimental during maturation of the cells. The recombination pro- science dates to Edward Jenner's successful vaccina- cess is initiated by the RAG proteins, and presence of tion against smallpox in 1796 (Jenner, 1798). The world- RAG genes during phylogeny identifies the evolutionary wide acceptance of vaccination led to mankind's great- time of appearance of the adaptive immune system, est achievements in preventing disease, and smallpox which is just past the appearance of vertebrates (Agra- is the first and only human disease that has been eradi- wal et al., 1998; Hiom et al., 1998). -
B-Cell Differentiation Is Pressuromodulated As Determined by Pressuromodulation Mapping: Part I, Cell Differentiation Hemant Sarin
Sarin Translational Medicine Communications (2018) 3:3 Translational Medicine https://doi.org/10.1186/s41231-018-0019-y Communications RESEARCH Open Access B-cell differentiation is pressuromodulated as determined by pressuromodulation mapping: Part I, cell differentiation Hemant Sarin Abstract Background: The episodic sub-episode block sums split-integrated weighted average-averaged gene overexpression tropy quotient (esebssiwaagoTQ) is a measure of the 5′ → 3′ reading direction intergene distance tropy that needs to be overcome for horizontal alignment of a gene for maximal transcription; and it is also an arbitrary unit measure of the intracellular pressure needed for maximal gene expression. In this study, B-cell differentiation is studied by esebssiwaagoTQ-based pressuromodulation mapping of B-cell stage marker genes. Methods: Locations of 25 B-cell differentiation stage genes, and locations of downstream and upstream genes were mined at GeneCards and at LNCipedia, pseudogenes included and enhancers excluded. The esebssiwaagoTQsforeach gene were determined. A pressuromodulation map was generated by arranging overexpressed B-cell stage marker genes in descending and ascending order by esebssiwaagoTQ in reference to periods of B-cell polarization. Results: The gene esebssiwaagoTQsareCD34 0.65 (0.648), PRDM1 0.36 (0.356), PTPRC 0.35 (0.345), MKI67 0.33 (0.329), ENPP1 0.31 (0.308), RAG2 0.31 (0.306), MS4A1 0.30 (0.299), PCNA 0.28 (0.285), ESPL1 0.28 (0.275), CD79B 0.27 (0.271), AICDA 0.27 (0.266), CD40 0.26 (0.257), APOBEC3A/-B 0.22 (0.216), CD38 0.21 (0.212), CD27 0.19 (0.194), APOBEC3C/−D/-F/−G 0.17 (0.173), CD19 0.15 (0.153), RAG1 0.14 (0.139), CD79A 0.14 (0.137), CR2 0.11 (0.109), and APOBEC3H 0.10 (0.102);theseare pressuromodulation mapped in reference to B-cell polarization state and differentiation stage.