Silencing and Transcriptional Regulation of Endogenous Retroviruses: an Overview
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Structure of the Tripartite Motif of KAP1/TRIM28 Identifies Molecular Interfaces Required for Transcriptional Silencing of Retrotransposons
bioRxiv preprint doi: https://doi.org/10.1101/505677; this version posted December 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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. Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons Guido A. Stoll1, Shun-ichiro Oda1, Zheng-Shan Chong1, Minmin Yu2, Stephen H. McLaughlin2 and Yorgo Modis1,* 1 Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK 2 MRC Laboratory oF Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK * Correspondence: [email protected] (Y.M.) Abstract Transcription oF transposable elements is tightly regulated to prevent damage to the genome. The family of KRAB domain-containing zinc Finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize speciFic retrotransposon sequences and recruit KAP1, which controls the assembly of an epigenetic silencing complex including histone H3K9 methyltransferase SETDB1. The chromatin remodeling activities of this complex repress transcription of the targeted transposable element and any adjacent genes. Here, we use biophysical and structural approaches to show that the tripartite motif (TRIM) of KAP1 Forms antiparallel dimers, which Further assemble into tetramers and higher-order oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 domain prevented higher-order oligomerization without a signiFicant loss oF retrotransposon silencing activity in a cell-based assay, indicating that, in contrast to other TRIM family members, selF-assembly is not essential For the function of KAP1. -
The Expression of Human Endogenous Retroviruses Is Modulated by the Tat Protein of HIV‐1
The Expression of Human Endogenous Retroviruses is modulated by the Tat protein of HIV‐1 by Marta Jeannette Gonzalez‐Hernandez A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Immunology) in The University of Michigan 2012 Doctoral Committee Professor David M. Markovitz, Chair Professor Gary Huffnagle Professor Michael J. Imperiale Associate Professor David J. Miller Assistant Professor Akira Ono Assistant Professor Christiane E. Wobus © Marta Jeannette Gonzalez‐Hernandez 2012 For my family and friends, the most fantastic teachers I have ever had. ii Acknowledgements First, and foremost, I would like to thank David Markovitz for his patience and his scientific and mentoring endeavor. My time in the laboratory has been an honor and a pleasure. Special thanks are also due to all the members of the Markovitz laboratory, past and present. It has been a privilege, and a lot of fun, to work near such excellent scientists and friends. You all have a special place in my heart. I would like to thank all the members of my thesis committee for all the valuable advice, help and jokes whenever needed. Our collaborators from the Bioinformatics Core, particularly James Cavalcoli, Fan Meng, Manhong Dai, Maureen Sartor and Gil Omenn gave generous support, technical expertise and scientific insight to a very important part of this project. Thank you. Thanks also go to Mariana Kaplan’s and Akira Ono’s laboratory for help with experimental designs and for being especially generous with time and reagents. iii Table of Contents Dedication ............................................................................................................................ ii Acknowledgements ............................................................................................................. iii List of Figures ................................................................................................................... -
Detection of HERV‑K6 and HERV‑K11 Transpositions in the Human Genome
BIOMEDICAL REPORTS 9: 53-59, 2018 Detection of HERV‑K6 and HERV‑K11 transpositions in the human genome BUKET CAKMAK GUNER1, ELIF KARLIK2, SEVGI MARAKLI1 and NERMIN GOZUKIRMIZI1 1Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, 34134 Istanbul; 2Department of Biotechnology, Institution of Science, Istanbul University, 34134 Istanbul, Turkey Received November 19, 2017; Accepted April 24, 2018 DOI: 10.3892/br.2018.1096 Abstract. Mobile genetic elements classed as transposons analysed HERV‑K movements among individuals. This is the comprise an estimated 45% of the human genome, and 8% of first report to investigate HERV‑K6 and HERV‑K11 retrotrans- these elements are human endogenous retroviruses (HERVs). poson polymorphisms between the genders and different age Endogenous retroviruses are retrotransposons, containing 5' groups. and 3' long terminal repeat sequences and encoding envelope, group‑specific antigen and DNA polymerase proteins. The Introduction aim of the present study was to analyse genome integration polymorphisms of HERV type K member 6 (HERV‑K6) and Human endogenous retroviruses (HERVs) belonging to the HERV‑K11 by using the retrotransposon based molecular superfamily of transposable and retrotransposable genetic marker technique, inter‑retrotransposon amplified polymor- elements represent ~8% of the human genome (1). HERV phism (IRAP). For this purpose, blood samples of 18 healthy type K (HERV‑K) is the sole group of endogenous retroviruses individuals within the age range of 10‑79 years (10 females that is established to contain human‑specific members. Group and 8 males) were collected, genomic DNAs were isolated HERV‑K (also known as human mouse mammary tumour and IRAP‑polymerase chain reaction (PCR) was performed. -
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. -
Ervmap Analysis Reveals Genome-Wide Transcription of INAUGURAL ARTICLE Human Endogenous Retroviruses
ERVmap analysis reveals genome-wide transcription of INAUGURAL ARTICLE human endogenous retroviruses Maria Tokuyamaa, Yong Konga, Eric Songa, Teshika Jayewickremea, Insoo Kangb, and Akiko Iwasakia,c,1 aDepartment of Immunobiology, Yale School of Medicine, New Haven, CT 06520; bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and cHoward Hughes Medical Institute, Chevy Chase, MD 20815 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2018. Contributed by Akiko Iwasaki, October 23, 2018 (sent for review August 24, 2018; reviewed by Stephen P. Goff and Nir Hacohen) Endogenous retroviruses (ERVs) are integrated retroviral elements regulates expression of IFN-γ–responsive genes, such as AIM2, that make up 8% of the human genome. However, the impact of APOL1, IFI6, and SECTM1 (16). ERV elements can drive ERVs on human health and disease is not well understood. While transcription of genes, generate chimeric transcripts with protein- select ERVs have been implicated in diseases, including autoim- coding genes in cancer, serve as splice donors or acceptors mune disease and cancer, the lack of tools to analyze genome- for neighboring genes, and be targets of recombination and in- wide, locus-specific expression of proviral autonomous ERVs has crease genomic diversity (17, 18). ERVs that are elevated in hampered the progress in the field. Here we describe a method breast cancer tissues correlate with the expression of granzyme called ERVmap, consisting of an annotated database of 3,220 hu- and perforin levels, implying a possible role of ERVs in immune man proviral ERVs and a pipeline that allows for locus-specific surveillance of tumors (19). -
DNA Recombination Is Sufficient for Retroviral Transduction JODY R
Proc. Natl. Acad. Sci. USA Vol. 92, pp. 2460-2464, March 1995 Biochemistry DNA recombination is sufficient for retroviral transduction JODY R. SCHWARTZ, Susi DUESBERG, AND PETER H. DUESBERG Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3206 Contributed by Peter H. Duesberg, November 28, 1994 ABSTRACT Oncogenic retroviruses carry coding se- quences that are transduced from cellular protooncogenes. Nat- env pOl X ural transduction involves two nonhomologous recombinations and is thus extremely rare. Since transduction has never been reproduced experimentall, its mechanism has been studied in terms oftwoehypotheses: (i) the DNAmodel,which postulates two ___ _-I ____ DNA recombinations, and (ii) the RNA model, which postulates a 5' DNA recombination and a 3' RNA recombination occurring during reverse transcription of viral and protooncogene RNA. proto-onc gene Here we use two viral DNA constructs to test the prediction ofthe DNA model that the 3' DNA recombination is achieved by conventional integration of a retroviral DNA 3' of the chromo- somal protooncogene coding region. For the DNA model to be ga-onc - gag viable, such recombinant viruses must be infectious without the w5 essential tract that precedes the 3' purportedly polypurine (ppt) FIG. 1. The DNA model of retroviral transduction. The model long terminal repeat (LTR) of all retroviruses. Our constructs proposes that the 5' retrovirus/protooncogene junction is achieved by consist ofa ras coding region from Harvey sarcoma virus which nonhomologous recombination between a circular provirus with a is naturally linked at the 5' end to a retroviral LTR and single LTR. Such proviruses are common in virus-infected cells (1). -
Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest. -
The LUCA and Its Complex Virome in Another Recent Synthesis, We Examined the Origins of the Replication and Structural Mart Krupovic , Valerian V
PERSPECTIVES archaea that form several distinct, seemingly unrelated groups16–18. The LUCA and its complex virome In another recent synthesis, we examined the origins of the replication and structural Mart Krupovic , Valerian V. Dolja and Eugene V. Koonin modules of viruses and posited a ‘chimeric’ scenario of virus evolution19. Under this Abstract | The last universal cellular ancestor (LUCA) is the most recent population model, the replication machineries of each of of organisms from which all cellular life on Earth descends. The reconstruction of the four realms derive from the primordial the genome and phenotype of the LUCA is a major challenge in evolutionary pool of genetic elements, whereas the major biology. Given that all life forms are associated with viruses and/or other mobile virion structural proteins were acquired genetic elements, there is no doubt that the LUCA was a host to viruses. Here, by from cellular hosts at different stages of evolution giving rise to bona fide viruses. projecting back in time using the extant distribution of viruses across the two In this Perspective article, we combine primary domains of life, bacteria and archaea, and tracing the evolutionary this recent work with observations on the histories of some key virus genes, we attempt a reconstruction of the LUCA virome. host ranges of viruses in each of the four Even a conservative version of this reconstruction suggests a remarkably complex realms, along with deeper reconstructions virome that already included the main groups of extant viruses of bacteria and of virus evolution, to tentatively infer archaea. We further present evidence of extensive virus evolution antedating the the composition of the virome of the last universal cellular ancestor (LUCA; also LUCA. -
TASOR Is a Pseudo-PARP That Directs HUSH Complex Assembly and Epigenetic Transposon Control
Lawrence Berkeley National Laboratory Recent Work Title TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Permalink https://escholarship.org/uc/item/6021r2cd Journal Nature communications, 11(1) ISSN 2041-1723 Authors Douse, Christopher H Tchasovnikarova, Iva A Timms, Richard T et al. Publication Date 2020-10-02 DOI 10.1038/s41467-020-18761-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE https://doi.org/10.1038/s41467-020-18761-6 OPEN TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control Christopher H. Douse 1,4,9, Iva A. Tchasovnikarova2,5,9, Richard T. Timms 2,9, Anna V. Protasio 2,6, Marta Seczynska2, Daniil M. Prigozhin 1,7, Anna Albecka1,2,8, Jane Wagstaff3, James C. Williamson2, ✉ ✉ Stefan M. V. Freund3, Paul J. Lehner 2 & Yorgo Modis 1,2 1234567890():,; The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits — TASOR, MPP8 and Periphilin — contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced tran- scriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA pro- cessing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. -
Effects of Retroviruses on Host Genome Function
ANRV361-GE42-20 ARI 1 August 2008 18:2 V I E E W R S I E N C N A D V A Effects of Retroviruses on Host Genome Function Patric Jern and John M. Coffin Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts 02111; email: [email protected], John.Coffi[email protected] Annu. Rev. Genet. 2008. 42:20.1–20.23 Key Words The Annual Review of Genetics is online at Human Endogenous Retrovirus, LTR, transcription, recombination, genet.annualreviews.org methylation This article’s doi: 10.1146/annurev.genet.42.110807.091501 Abstract Copyright c 2008 by Annual Reviews. For millions of years, retroviral infections have challenged vertebrates, All rights reserved occasionally leading to germline integration and inheritance as ERVs, 0066-4197/08/1201-0001$20.00 genetic parasites whose remnants today constitute some 7% to 8% of the human genome. Although they have had significant evolutionary side effects, it is useful to view ERVs as fossil representatives of retro- viruses extant at the time of their insertion into the germline, not as direct players in the evolutionary process itself. Expression of particu- lar ERVs is associated with several positive physiological functions as well as certain diseases, although their roles in human disease as etio- logical agents, possible contributing factors, or disease markers—well demonstrated in animal models—remain to be established. Here we discuss ERV contributions to host genome structure and function, in- cluding their ability to mediate recombination, and physiological effects on the host transcriptome resulting from their integration, expression, and other events. -
The Evolutionary Life History of P Transposons: from Horizontal Invaders to Domesticated Neogenes
Chromosoma (2001) 110:148–158 DOI 10.1007/s004120100144 CHROMOSOMA FOCUS Wilhelm Pinsker · Elisabeth Haring Sylvia Hagemann · Wolfgang J. Miller The evolutionary life history of P transposons: from horizontal invaders to domesticated neogenes Received: 5 February 2001 / In revised form: 15 March 2001 / Accepted: 15 March 2001 / Published online: 3 May 2001 © Springer-Verlag 2001 Abstract P elements, a family of DNA transposons, are uct of their self-propagating lifestyle. One of the most known as aggressive intruders into the hitherto uninfected intensively studied examples is the P element of Dro- gene pool of Drosophila melanogaster. Invading through sophila, a family of DNA transposons that has proved horizontal transmission from an external source they useful not only as a genetic tool (e.g., transposon tag- managed to spread rapidly through natural populations ging, germline transformation vector), but also as a model within a few decades. Owing to their propensity for rapid system for investigating general features of the evolu- propagation within genomes as well as within popula- tionary behavior of mobile DNA (Kidwell 1994). P ele- tions, they are considered as the classic example of self- ments were first discovered as the causative agent of hy- ish DNA, causing havoc in a genomic environment per- brid dysgenesis in Drosophila melanogaster (Kidwell et missive for transpositional activity. Tracing the fate of P al. 1977) and were later characterized as a family of transposons on an evolutionary scale we describe differ- DNA transposons -
THE POSSIBLE ROLE of ENDOGENOUS RETROVIRUSES in TUMOUR DEVELOPMENT & INNATE SIGNALLING by EMMANUEL ATANGANA MAZE a Thesis Su
University of Plymouth PEARL https://pearl.plymouth.ac.uk 04 University of Plymouth Research Theses 01 Research Theses Main Collection 2018 THE POSSIBLE ROLE OF ENDOGENOUS RETROVIRUSES IN TUMOUR DEVELOPMENT AND INNATE SIGNALLING Atangana Maze, Emmanuel http://hdl.handle.net/10026.1/13081 University of Plymouth All content in PEARL is protected by copyright law. Author manuscripts are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author. THE POSSIBLE ROLE OF ENDOGENOUS RETROVIRUSES IN TUMOUR DEVELOPMENT & INNATE SIGNALLING by EMMANUEL ATANGANA MAZE A thesis submitted to the University of Plymouth in partial fulfilment for the degree of DOCTOR OF PHILOSOPHY School of Biomedical Sciences 2018 COPYRIGHT STATEMENT This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognize that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the author’s prior consent. 2 THE POSSIBLE ROLE OF ENDOGENOUS RETROVIRUSES IN TUMOUR DEVELOPMENT & INNATE SIGNALLING by EMMANUEL ATANGANA MAZE UNIVERSITY OF PLYMOUTH School of Biomedical Sciences 2018 3 “You are the light of the world. A town built on a hill cannot be hidden. Neither do people light a lamp and put it under a bowl. Instead they put it on its stand, and it gives light to everyone in the house.