DOCSLIB.ORG

Nested Retrotransposition in the East Asian Mouse Genome Causes the Classical Nonagouti Mutation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

ARTICLE https://doi.org/10.1038/s42003-019-0539-7 OPEN Nested retrotransposition in the East Asian mouse genome causes the classical nonagouti mutation Akira Tanave1,3, Yuji Imai1 & Tsuyoshi Koide 1,2 1234567890():,; Black coat color (nonagouti) is a widespread classical mutation in laboratory mouse strains. The intronic insertion of endogenous retrovirus VL30 in the nonagouti (a) allele of agouti gene was previously reported as the cause of the nonagouti phenotype. Here, we report agouti mouse strains from East Asia that carry the VL30 insertion, indicating that VL30 alone does not cause the nonagouti phenotype. We find that a rare type of endogenous retrovirus, β4, was integrated into the VL30 region at the a allele through nested retrotransposition, causing abnormal splicing. Targeted complete deletion of the β4 element restores agouti gene expression and agouti coat color, whereas deletion of β4 except for a single long terminal repeat results in black-and-tan coat color. Phylogenetic analyses show that the a allele and the β4 retrovirus originated from an East Asian mouse lineage most likely related to Japanese fancy mice. These findings reveal the causal mechanism and historic origin of the classical nonagouti mutation. 1 Mouse Genomics Resource Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan. 2 Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), 1111 Yata, Mishima, Shizuoka 411-8540, Japan. 3Present address: Laboratory for Mouse Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 1–3 Yamadaoka, Suita, Osaka 565-0871, Japan. Correspondence and requests for materials should be addressed to T.K. (email: [email protected]) COMMUNICATIONS BIOLOGY | (2019) 2:283 | https://doi.org/10.1038/s42003-019-0539-7 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-019-0539-7 oat color mutations are common in laboratory animals. a 20 kb The reference laboratory mouse strain C57BL/6 (B6) Exon 1A1A′ 1B/1C 234 C a carries the nonagouti (a) mutation at the agouti locus. The B6 coloration of each hair in the agouti (A) mouse, the so-called wild b type, shows unique hair pigmentation banded in a pattern of 1 2914 12,251 14,701 bp black-yellow-black from the root to the tip, whereas nonagouti VL30 Unknown VL30 (a/a) mice exhibit simple black hairs. From the early days of 3′ LTR 5′ DTR 3′ DTR 5′ LTR genetic studies after the rediscovery of Mendel’s law, many c researchers have been interested in the inheritance of the various LTR alleles at the agouti locus, including the a allele, because of its ease ′ of detection, high penetrance, and large number of available 4.0 genetic resources1,2. More than 100 mutations at the agouti locus 2.0 have been reported in the Mouse Genome Informatics (MGI) Ref VL30 version 6.12 database, and the a allele is broadly distributed in a LTR 3 ′ 0.0 kb variety of inbred strains listed in the International Mouse 5 0.02.0 4.0 6.0 8.0 10.0 12.0 14.0 kb Strain Resource (IMSR). These nonagouti mutants have been used for a variety of studies, such as analyses of the mechanism Fig. 1 Structure of inserted sequence in the a allele. a, b Schematic of pigmentation, melanosome function and its mechanism representation of the genomic structure of the a allele of the agouti gene (a) of gene regulation, and associations between coat color and and the inserted sequence (b) in the B6 mouse. The B6 reference genome behaviors1,3–6. Therefore, the nonagouti mutation remains useful sequence (14,705 bp in length on chr2:155,014,951–155,029,655 in in many research fields. GRCm38/mm10 assembly) was used to analyze the inserted sequence. The a allele is characterized by a hypomorphic mutation of the c Comparison of the inserted sequence in the a allele (horizontal axis) and agouti gene, which encodes a paracrine signaling molecule called the reference VL30 sequence (X17124.1; vertical axis). Scale bar = 20 kb. agouti signaling protein (ASIP or ASP), and the reduced ASIP is LTR, long terminal repeat; DTR, direct terminal repeat not sufficient for switching between the synthesis of eumelanin (black or brown) pigment to that of pheomelanin (yellow) pig- additional sequence (hereafter referred to as the unknown ele- ment. Thus, eumelanin is the predominant pigment in the mel- ment) internally at position 2914 in the VL30 sequence. The anocytes within the hair follicle in B6 mice1,3. The agouti gene, length of the unknown element within VL30 was thus longer than located on chromosome 2, is composed of seven exons. A pre- that estimated in a previous report4. vious genetic study proposed that an insertion of 11 kb in the intron lying downstream of the agouti exon 1C causes the non- agouti phenotype in a/a mice4. The structure of the inserted Nested insertion of an endogenous retrovirus within VL30. The sequence is complex and was estimated to consist of 5.5 kb of presence of a 4-bp direct duplication, also called a target site virus-like 30S (VL30) sequence, belonging to one of the murine duplication, flanking the VL30 element is thought to be evidence endogenous retroviruses, as well as incorporating 5.5 kb of of a retroviral insertion in the a allele of the agouti gene (Fig. 2a)4. additional unknown sequence internally. The VL30 insertion Similarly, we identified a 6-bp direct duplication of a part of the could be mutagenic to the agouti gene, as such sequences can act VL30 sequence on either side of the unknown element (Fig. 2a), as a target of epigenetic silencing7, but the actual molecular implying that the unknown element was inserted into the mechanism underlying the decline in agouti gene expression VL30 sequence through a mechanism similar to the integration of remains unknown. Furthermore, the molecular nature and evo- retroviral sequence8. In support of this idea, we found a com- lutionary process responsible for the internal, unknown sequence pletely identical direct terminal repeat of 522 bp at both ends within the VL30 element still remains to be clarified. lying just inside the 6-bp direct duplication sequence. A sequence Here, we characterized the molecular structure of the 11 kb (GenBank ID: AB242436) homologous to the unknown element sequence inserted into the agouti gene. We found that the internal has been reported and derives from the inserted sequence in the sequence is a rare type of endogenous retrovirus, β4, which was piebald (s) allele of the endothelin receptor type B (Ednrb) gene integrated into the VL30 sequence through nested retro- (Ednrbs) in Japanese fancy mouse strain JF1/Ms (JF1) (Fig. 2b)9. transposition. Deletion of the internal β4 in a nonagouti strain In order to predict the functional significance of the direct using the CRISPR/Cas9 method caused reversion of the wild-type terminal repeats in the unknown element, we searched for agouti phenotype, whereas deletion of the β4 except for a single homologous RNA sequences within the National Center for long terminal repeat (LTR) sequence resulted in a black-and-tan Biotechnology Information (NCBI) Mus musculus Annotation coat color. These results clearly demonstrate that the nested Release 106 using BLASTN (version 2.8.0 + ). Among these RNA retrotransposition of the β4 is the true cause behind the classical sequences, we found eight genes that contain sequence homo- nonagouti mutation. Furthermore, we found that the retro- logous to the direct terminal repeat (C6, Fuca1, Gimap3, Nyx transposition of β4 was present in Japanese fancy mice, through and Serpina3a mRNAs; Mir680-1, Mir680-2, and Mir680-3 which it was likely introduced into many laboratory strains. This microRNAs). Based on available expression sequence tags and study provides a clear scenario concerning the origin of one of the full-length cDNAs from mouse and experimental evidence from most famous classical mouse mutations. the Ednrbs gene8, we identified a transcription start site and a termination site on the sense strand of the homologous sequences (Supplementary Fig. 1). For instance, the direct terminal repeats Results in the unknown element were homologous to a 518-bp sequence Genomic structure of the nonagouti allele.Wefirst character- composed of the first exon and the flanking downstream regions ized in detail the structure of the inserted sequence in the a of the Serpina3a gene (93.1% identity), a 518-bp sequence com- allele based on the B6 reference genome sequence (Fig. 1a–c). posed of the last exon and the flanking upstream regions of the We found that the inserted sequence consists of 5357 bp of C6 gene (87.4% identity), and a 507-bp sequence composed of the VL30 sequence in an antisense orientation relative to the direc- last exon and the flanking upstream regions of the abnormal tion of agouti gene transcription, interrupted by 9344 bp of transcript of the Ednrbs gene (96.0% identity). It is known that the 2 COMMUNICATIONS BIOLOGY | (2019) 2:283 | https://doi.org/10.1038/s42003-019-0539-7 | www.nature.com/commsbio COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-019-0539-7 ARTICLE a d 1 9338 bp A 5′ 3′ a 5′ 3′ Unknown ATG 3′ LTR 5′ LTR Gm14226 VL30Unknown VL30 Ref VL30 3′ 5′ a 5′ 3′ 5′ LTR gag propol env 3′ LTR 2 kb 5′ DTR 3′ DTR e Gypsy Erranti VL30Unknown VL30 PFV-1 77 WDSV 85 100 MDEV MmERV 91 b 100 GaLV KoRV 90 99 FeLV DR ′ MoMLV 100 70 PERV-A BaEV SNV HTLV-I HIV-1 Lenti 100 83 ALV 97 RSV 2.0 kb 83 GgERV-K10 Transposon-like Python_molorus_ERV 92 79 MmIAPEYI 97 MIAP 97 DR 3 ′ 97 MaIAP 5 0.0 4.0 0.5 subs./site MmERV-K10c 0.02.0 4.0 6.0 8.0 kb HERV-K10 MMTV (2) 91 MmERV- 1_NT_039714 MusD (7) Unknown ENTV (3) ′ ′ 100 JSRV ( 3) 5 DTR 3 DTR SERV (6) -like SRV-2 (6) 100 MPMV (6) 100 SRV-1 (6) c 90 SMRV (5) ′ MmERV- 5_AC098708 5′DTR 16 nt PBS PPT 3 DTR 100 MmERV- 4_AC110500 MmERV- 4_AC124523 TvERV-D (4) 96 522 bp 522 bp M_murinus_ERV- 4_AC145758 Lys-tRNA 82 MmERV-4_AC102561 3′ 5′ 72 100 Unknown Fig.
Recommended publications
  • Illegitimate DNA Integration in Mammalian Cells

    Illegitimate DNA Integration in Mammalian Cells

    Gene Therapy (2003) 10, 1791–1799 & 2003 Nature Publishing Group All rights reserved 0969-7128/03 $25.00 www.nature.com/gt REVIEW Illegitimate DNA integration in mammalian cells HWu¨ rtele1, KCE Little2 and P Chartrand2,3 1Programme de Biologie Mole´culaire, Universite´ de Montre´al, Montre´al, Canada; 2Department of Medicine, Division of Experimental Medicine, McGill University, Montre´al, Que´bec, Canada; and 3Centre Hospitalier de l’Universite´ de Montre´al and De´partement de Pathologie et de Biologie Cellulaire, Universite´ de Montre´al, Montre´al, Que´bec, Canada Foreign DNA integration is one of the most widely exploited therapy procedures can result in illegitimate integration of cellular processes in molecular biology. Its technical use introduced sequences and thus pose a risk of unforeseeable permits us to alter a cellular genome by incorporating a genomic alterations. The choice of insertion site, the degree fragment of foreign DNA into the chromosomal DNA. This to which the foreign DNA and endogenous locus are modified process employs the cell’s own endogenous DNA modifica- before or during integration, and the resulting impact on tion and repair machinery. Two main classes of integration structure, expression, and stability of the genome are all mechanisms exist: those that draw on sequence similarity factors of illegitimate DNA integration that must be con- between the foreign and genomic sequences to carry out sidered, in particular when designing genetic therapies. homology-directed modifications, and the nonhomologous or Gene Therapy (2003) 10, 1791–1799. doi:10.1038/ ‘illegitimate’ insertion of foreign DNA into the genome. Gene sj.gt.3302074 Keywords: illegitimate DNA integration; DNA repair; transgenesis; recombination; mutagenesis Introduction timate integration.
  • Structure of the Tripartite Motif of KAP1/TRIM28 Identifies Molecular Interfaces Required for Transcriptional Silencing of Retrotransposons

    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.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    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.
  • The Human Genome Project

    The Human Genome Project

    TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 Contents FOREWORD . 2 THE GENOME PROJECT—WHY THE DOE? . 4 A bold but logical step INTRODUCING THE HUMAN GENOME . 6 The recipe for life Some definitions . 6 A plan of action . 8 EXPLORING THE GENOMIC LANDSCAPE . 10 Mapping the terrain Two giant steps: Chromosomes 16 and 19 . 12 Getting down to details: Sequencing the genome . 16 Shotguns and transposons . 20 How good is good enough? . 26 Sidebar: Tools of the Trade . 17 Sidebar: The Mighty Mouse . 24 BEYOND BIOLOGY . 27 Instrumentation and informatics Smaller is better—And other developments . 27 Dealing with the data . 30 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS . 32 An essential dimension of genome research Foreword T THE END OF THE ROAD in Little has been rapid, and it is now generally agreed Cottonwood Canyon, near Salt that this international project will produce Lake City, Alta is a place of the complete sequence of the human genome near-mythic renown among by the year 2005. A skiers. In time it may well And what is more important, the value assume similar status among molecular of the project also appears beyond doubt. geneticists. In December 1984, a conference Genome research is revolutionizing biology there, co-sponsored by the U.S. Department and biotechnology, and providing a vital of Energy, pondered a single question: Does thrust to the increasingly broad scope of the modern DNA research offer a way of detect- biological sciences.
  • A KAP1 Phosphorylation Switch Controls Myod Function During Skeletal Muscle Differentiation

    A KAP1 Phosphorylation Switch Controls Myod Function During Skeletal Muscle Differentiation

    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation Kulwant Singh,1,5 Marco Cassano,2,5 Evarist Planet,2 Soji Sebastian,1 Suk Min Jang,2 Gurjeev Sohi,1 Herve Faralli,1 Jinmi Choi,3 Hong-Duk Youn,3 F. Jeffrey Dilworth,1,4 and Didier Trono2 1Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; 2School of Life Sciences, Ecole Polytechnique Fed erale de Lausanne (EPFL), 1015 Lausanne, Switzerland; 3Department of Biomedical Sciences and Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea; 4Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Kruppel-like€ associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome.
  • Fancy Mice, Their Varieties and Management As Pets Or for Show, Including the Latest Scientific Information As to Breeding for C

    Fancy Mice, Their Varieties and Management As Pets Or for Show, Including the Latest Scientific Information As to Breeding for C

    .S o p^ ^-» ^ o0) C/5 g •H o E - o TO C o •H (ii Q OJ OS 'Lf\ r-i fc VN XjA C\J CTn CO _3 S O (-1 2yC:J.Davies -\V ONE & ALL SEEDS, 5 FANCY MICE. Cornell University Library The original of tliis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31 924001 01 3246 : FANCY MICE Their Varieties and Management as Pets or for Show. Including the latest Scientific Information as to Breeding for Colour. Fifth Edition, Completely Revised, By C. J. DAVIES. ILLUSTRATED. LONDON L. UPCOTT GILL, Bazaar Buildings, Drury Lane, W.C. 1912. Books for Fanciers. Each Is. net, by post Is. 2d. The Management of Rabbits. Third edition, revised and enlarged by Meredith ^^ Fradd. DOMESTrC AND FANCY CATS; including the Points of Show Varieties, Preparing for Exhibition and Treatment for ; the Diseases and Parasites. By John Jennings. English and Welsh Terriers. Their Uses, Points, and Show Preparation. By J Maxtee. Scotch and Irish Terriers. With chapters on the Housing, Training, and minor Diseases of Terriers in general. A companion handbook to the above. Diseases of Dogs, a very practical handbook which every Dog-Owner should have at hand. Fourth edition, revised by A. C. PiESSE, M.R.C.V.S. Pet Monkeys, a complete and excellent book by Arthur H. Patterson, A.M.B.A. Second edition. Pigeon-Keeping for Amateurs. Describing practically all varieties of Pigeons. By James C.
  • Genetics As Explanation: Limits to the Human Genome Project’ (2006, 2009)

    Genetics As Explanation: Limits to the Human Genome Project’ (2006, 2009)

    els a0026653.tex V2 - 08/29/2016 4:00 P.M. Page 1 Version 3 a0026653 Genetics as Explanation: Introductory article Article Contents Limits to the Human • Definitions • Metaphors and Programs Genome Project • Metaphors and Expectations • Genome is Not a Simple Program Irun R Cohen, The Weizmann Institute of Science, Rehovot, Israel • Microbes, Symbiosis and the Holobiont Henri Atlan, Ecole des Hautes Etudes en Sciences Sociales, Paris, France and Hadas- • Stem Cells Express Multiple Genes • sah University Hospital, Jerusalem, Israel Meaning: Line or Loop? AU:1 • Self-Organisation and Program Sol Efroni, Bar-Ilan University, Ramat Gan, Israel • Complexity, Reduction and Emergence • Evolving Genomes AU:2 Based in part on the previous versions of this eLS article ‘Genetics as Explanation: Limits to the Human Genome Project’ (2006, 2009). • The Environment and the Genome • Language Metaphor • Tool and Toolbox Metaphors • Conclusion Online posting date: 14th October 2016 Living organisms are composed of cells and all biological evolution, single organisms, populations of organisms, living cells contain a genome, the organism’s stock species, cells and molecules, heredity, embryonic development, of deoxyribonucleic acid (DNA). The role of the health and disease and life management. These are quite diverse genome has been likened to a computer program subjects, and the people who study them would seem to use the term gene in distinctly different ways. But genetics as a whole that encodes the organism’s development and its is organised by a single unifying principle, the deoxyribonucleic subsequent response to the environment. Thus, the acid (DNA) code; all would agree that the information borne by organism and its fate can be explained by genetics, a gene is linked to particular sequences of DNA.
  • Hippocampal Dysfunction in the Euchromatin Histone Methyltransferase 1 Heterozygous Knockout Mouse Model for Kleefstra Syndrome

    Hippocampal Dysfunction in the Euchromatin Histone Methyltransferase 1 Heterozygous Knockout Mouse Model for Kleefstra Syndrome

    Human Molecular Genetics, 2013, Vol. 22, No. 5 852–866 doi:10.1093/hmg/dds490 Advance Access published on November 21, 2012 Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome Monique C.M. Balemans1,2, Nael Nadif Kasri3, Maksym V. Kopanitsa5, Nurudeen O. Afinowi5, Ger Ramakers6, Theo A. Peters4, Andy J. Beynon4, Sanne M. Janssen1, Rik C.J. van Summeren1,2, Jorine M. Eeftens1, Nathalie Eikelenboom1, Marco Benevento3, Makoto Tachibana7, Yoichi Shinkai7, Tjitske Kleefstra1, Hans van Bokhoven1,3,∗,{ and Catharina E.E.M. Van der Zee2,∗,{ 1Department of Human Genetics, 2Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, 3Department of Cognitive Neurosciences, and 4Department of Otorhinolaryngology, Donders Institute for Brain, Downloaded from Cognition and Behavior, Radboud University, Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands 5Synome Ltd, Moneta Building, Babraham Research Campus, Cambridge CB22 3AT, UK, 6Department of Developmental Psychology, University of Amsterdam, Roetersstraat 15, 1018 WB Amsterdam, the Netherlands and 7Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto, University, 53 Shogoin, http://hmg.oxfordjournals.org/ Kawara-cho, Sakyo-ku, Kyoto, Japan Received October 21, 2012; Revised October 21, 2012; Accepted November 15, 2012 Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intel- lectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. by guest on March 24, 2016 Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin his- tone methyltransferase 1 heterozygous knockout (Ehmt11/2) mice as a model for KS.
  • The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes

    The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes

    The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes Patrick L. Collinsa, Katherine E. Kylea, Takeshi Egawaa, Yoichi Shinkaib, and Eugene M. Oltza,1 aDepartment of Pathology, Washington University School of Medicine, St. Louis, MO 63110; and bCellular Memory Laboratory, RIKEN, Saitama 351-0198, Japan Edited by John V. Moran, University of Michigan, Ann Arbor, MI, and accepted by the Editorial Board May 21, 2015 (received for review November 19, 2014) Genome stability relies on epigenetic mechanisms that enforce tumor viruses (MMTVs). Reintegration of these expressed viruses repression of endogenous retroviruses (ERVs). Current evidence can generate mutations with potential oncogenic consequences suggests that distinct chromatin-based mechanisms repress ERVs (7). Thus, suppression of ERVs via epigenetic mechanisms is es- in cells of embryonic origin (histone methylation dominant) vs. pecially important in adult tissues that harbor cells with a high more differentiated cells (DNA methylation dominant). However, proliferative capacity. the latter aspect of this model has not been tested. Remarkably, Recent studies suggest that the mechanisms of ERV re- and in contrast to the prevailing model, we find that repressive pression in differentiated adult tissues are distinct from those histone methylation catalyzed by the enzyme SETDB1 is critical for in embryonic stem cells (ESCs) or early lineage progenitors (3). In fully differentiated cells, such as fibroblasts, DNA methylation suppression of specific ERV families and exogenous retroviruses in appears to be particularly important for ERV suppression, committed B-lineage cells from adult mice. The profile of ERV whereas HMTs responsible for H3K9me3 are largely dispens- activation in SETDB1-deficient B cells is distinct from that observed able (3, 4).
  • Connecting Myelin-Related and Synaptic Dysfunction In

    Connecting Myelin-Related and Synaptic Dysfunction In

    www.nature.com/scientificreports OPEN Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich Received: 24 October 2016 Accepted: 27 February 2017 gene expression hubs Published: 07 April 2017 Hedi Hegyi Combining genome-wide mapping of SNP-rich regions in schizophrenics and gene expression data in all brain compartments across the human life span revealed that genes with promoters most frequently mutated in schizophrenia are expression hubs interacting with far more genes than the rest of the genome. We summed up the differentially methylated “expression neighbors” of genes that fall into one of 108 distinct schizophrenia-associated loci with high number of SNPs. Surprisingly, the number of expression neighbors of the genes in these loci were 35 times higher for the positively correlating genes (32 times higher for the negatively correlating ones) than for the rest of the ~16000 genes. While the genes in the 108 loci have little known impact in schizophrenia, we identified many more known schizophrenia-related important genes with a high degree of connectedness (e.g. MOBP, SYNGR1 and DGCR6), validating our approach. Both the most connected positive and negative hubs affected synapse-related genes the most, supporting the synaptic origin of schizophrenia. At least half of the top genes in both the correlating and anti-correlating categories are cancer-related, including oncogenes (RRAS and ALDOA), providing further insight into the observed inverse relationship between the two diseases. Gene expression correlation, protein-protein interaction and other high-throughput experiments in the post-genomic era have revealed that genes tend to form complex, scale-free networks where most genes have a few connections with others and a few have a high number of interactions, commonly referred to as “hubs”, estab- lishing them as important central genes in these gene networks1.
  • A New Entrez Database Transitioning from Locuslink to Entrez

    A New Entrez Database Transitioning from Locuslink to Entrez

    NCBI News National Center for Biotechnology Information National Library of Medicine National Institutes of Health Spring 2004 Department of Health and Human Services Transitioning from LocusLink to Entrez Gene Cancer Chromosomes: a New Entrez Database A gene-based view of annotated The Entrez Gene help document genomes is essential to capitalize on provides tips to ease the transition Three databases, the NCI/NCBI the increase in the sequencing and for LocusLink users to the current SKY (Spectral Karyotyping)/M- analysis of model genomes. The Entrez Gene database. FISH (Multiplex-FISH) and CGH Entrez Gene database has been (Comparative Genomic The default display format for developed to supply key connections Hybridization) Database, the NCI Entrez Gene is the graphics display between maps, sequences, expression Mitelman Database of Chromosome shown in Figure 1 for BMP7, which profiles, structure, function, homolo- Aberrations in Cancer, and the NCI resembles the traditional view of a gy data, and the scientific literature. Recurrent Chromosome Aberrations LocusLink record. The array of col- Unique identifiers are assigned to in Cancer databases are now integrat- ored boxes at the head of LocusLink genes with defining sequence, genes ed into NCBI’s Entrez system as the reports that provide links to gene- with known map positions, and “Cancer Chromosomes” database. related resources is replaced by the genes inferred from phenotypic Cancer Chromosomes supports “Links” menu in Gene, which information. These gene identifiers searches for cytogenetic, clinical, or includes additional links, such as are tracked, and functional informa- reference information using the flexi- those to Books, GEO, UniSTS, and tion is added when available.
  • Functional Dependency Analysis Identifies Potential Druggable

    Functional Dependency Analysis Identifies Potential Druggable

    cancers Article Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia 1, 1, 2 3 Yujia Zhou y , Gregory P. Takacs y , Jatinder K. Lamba , Christopher Vulpe and Christopher R. Cogle 1,* 1 Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610-0278, USA; yzhou1996@ufl.edu (Y.Z.); gtakacs@ufl.edu (G.P.T.) 2 Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610-0278, USA; [email protected]fl.edu 3 Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0278, USA; cvulpe@ufl.edu * Correspondence: [email protected]fl.edu; Tel.: +1-(352)-273-7493; Fax: +1-(352)-273-5006 Authors contributed equally. y Received: 3 November 2020; Accepted: 7 December 2020; Published: 10 December 2020 Simple Summary: New drugs are needed for treating acute myeloid leukemia (AML). We analyzed data from genome-edited leukemia cells to identify druggable targets. These targets were necessary for AML cell survival and had favorable binding sites for drug development. Two lists of genes are provided for target validation, drug discovery, and drug development. The deKO list contains gene-targets with existing compounds in development. The disKO list contains gene-targets without existing compounds yet and represent novel targets for drug discovery. Abstract: Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ).