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4 results on '"MESH: DNA Transposable Elements/genetics"'

1. Necroptosis microenvironment directs lineage commitment in liver cancer

Author

Rishabh Chawla, Lisa Hoenicke, Nir Rozenblum, Jule Harbig, Johannes Zuber, Marco Seehawer, Gregory J. Dore, Hien Dang, Pierre-François Roux, Florian Heinzmann, Mihael Vucur, Thomas Longerich, Tom Luedde, Bence Sipos, Oliver Bischof, Tae-Won Kang, Xin Wei Wang, Lucas Robinson, Mathias Heikenwalder, Sabrina Klotz, Mareike Roth, Thorsten Buch, Luana D’Artista, Lars Zender, Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Universität Zürich [Zürich] = University of Zurich (UZH), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Vienna Biocenter - VBC [Austria], University of Tübingen, Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Cancer Consortium [Heidelberg] (DKTK), This work was supported by the ERC Consolidator Grant ‘CholangioConcept’ (to L.Z.), the German Research Foundation (DFG): grants FOR2314, SFB685, SFB/TR209 and the Gottfried Wilhelm Leibniz Program (to L.Z.). Further funding was provided by the German Ministry for Education and Research (BMBF) (e:Med/Multiscale HCC), the German Universities Excellence Initiative (third funding line: ‘future concept’), the German Center for Translational Cancer Research (DKTK), the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (to L.Z.) and the Intramural Research Program of the Centre for Cancer Research, National Cancer Institute, National Institutes of Health (to X.W.W.). The group of O.B. is supported by grants from ANR-BMFT, Fondation ARC pour la recherche sur le Cancer, INSERM, and the National Cancer Institute of the National Institutes of Health under Award Number R01CA136533. O.B. is a CNRS fellow., We thank E. Rist, P. Schiemann, C. Fellmeth, C.-J. Hsieh, D. Heide and J. Hetzer for technical help or assistance. We thank A. Weber for providing TLR2 and TLR4 knockout mice and W. S. Alexander and The Walter and Eliza Hall Institute of Medical Research for providing Mlklfl/fl mice. The Cas9n–p19Arf sgRNA vector was provided by W. Xue. We thank the c.ATG facility of Tuebingen University and CeGaT Tuebingen for exome sequencing and data analysis., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), University of Zurich, and Zender, Lars

Subjects
0301 basic medicine, MESH: Necrosis*/genetics, Cellular differentiation, MESH: Cell Lineage*/genetics, MESH: Carcinoma, Hepatocellular/pathology, MESH: Tumor Microenvironment, 10239 Institute of Laboratory Animal Science, MESH: Animals, Cancer epigenetics, MESH: Apoptosis*/genetics, MESH: Transcription Factors/metabolism, MESH: Proto-Oncogene Proteins c-akt/genetics, Multidisciplinary, MESH: Carcinoma, Hepatocellular/genetics, MESH: Cyclin-Dependent Kinase Inhibitor p16/deficiency, 3. Good health, MESH: Carcinogenesis/genetics, MESH: Cholangiocarcinoma/genetics, MESH: Mosaicism, MESH: T-Box Domain Proteins/genetics, Liver cancer, Cancer microenvironment, MESH: Cell Differentiation, Necroptosis, MESH: Cholangiocarcinoma/pathology, MESH: Liver Neoplasms/pathology, Context (language use), 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: DNA-Binding Proteins/metabolism, Article, 03 medical and health sciences, MESH: DNA Transposable Elements/genetics, MESH: Gene Expression Profiling, MESH: Hepatocytes/metabolism, medicine, MESH: Transcription Factors/genetics, MESH: Mice, MESH: Genes, myc, MESH: Liver Neoplasms/genetics, Tumor microenvironment, 1000 Multidisciplinary, MESH: DNA-Binding Proteins/genetics, MESH: Humans, Epigenome, medicine.disease, MESH: Male, digestive system diseases, MESH: Genes, ras, 030104 developmental biology, MESH: Hepatocytes/pathology, Cancer research, Hepatic stellate cell, 570 Life sciences, biology, MESH: Epigenesis, Genetic/genetics, MESH: Cytokines/metabolism, MESH: Disease Models, Animal, MESH: Female, MESH: T-Box Domain Proteins/metabolism
Abstract

Comment in :- Neighbourhood deaths cause a switch in cancer subtype. [Nature. 2018]- Neighbourly deaths dictate fate. [Nat Rev Cancer. 2018]- Bad neighborhoods: apoptotic and necroptotic microenvironments determine liver cancer subtypes. [Hepatobiliary Surg Nutr. 2019]- Viewpoint: necroptosis influences the type of liver cancer via changes of hepatic microenvironment. [Hepatobiliary Surg Nutr. 2019]; International audience; Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.

Published
2018
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2. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

Author

Linda Dowd, Theresa Feltwell, Tracey Chillingworth, Stephen Baker, Zahra Hance, Brendan W. Wren, Richard A. Stabler, Nicholas R. Thomson, S. Holroyd, Anne Wright, Audrey Fraser, Sarah Sharp, Adam P. Roberts, Karen Brooks, Michael A. Quail, K. Stevens, Kay Jagels, Peter Mullany, Louise Unwin, Paul Davis, Hongmei Wang, Claire Price, Bart Barrell, Carol Churcher, Ann Cronin, Matthew T. G. Holden, Ana Cerdeño-Tárraga, Nathalie Bason, Neil F. Fairweather, Karen Mungall, Mark Simmonds, Nigel P. Minton, Julian Parkhill, Ester Rabbinowitsch, Sally Whithead, Gordon Dougan, Bruno Dupuy, Mohammed Sebaihia, Sharon Moule, The Wellcome Trust Sanger Institute [Cambridge], Department of Infectious and Tropical Diseases (LSHTM), London School of Hygiene and Tropical Medicine (LSHTM), Eastman Dental Institute [UCL, London], University College of London [London] (UCL), MRC Centre for Molecular Microbiology and Infection [Imperial College, London] (CMBI), Imperial College London, Centre for Biomolecular Sciences [Nottingham, UK] (CBS), University of Nottingham, UK (UON), Génétique Moléculaire Bactérienne, Institut Pasteur [Paris] (IP), This work was supported by the Wellcome Trust., We would like to acknowledge the support of the Wellcome Trust Sanger Institute core sequencing and informatics groups. We thank D. Gerding and G. Songer for provision of C. difficile strains, F. Barbut and J. Emerson for help with the antibiotic susceptibility tests, and the BUGs microarray facility at St. George's Hospital for provision of the C. difficile 630 microarray., and Institut Pasteur [Paris]

Subjects
[SDV]Life Sciences [q-bio], MESH: Base Sequence, MESH: Genome, Bacterial, Genome, Drug Resistance, Multiple, Bacterial, MESH: Clostridium difficile/pathogenicity, MESH: Clostridium difficile/physiology, MESH: Spores, Bacterial/physiology, Enterocolitis, Pseudomembranous, MESH: Gastrointestinal Tract/microbiology, Oligonucleotide Array Sequence Analysis, Spores, Bacterial, Genetics, 0303 health sciences, Virulence, Mosaicism, Clostridium difficile, MESH: Enterocolitis, Pseudomembranous/etiology, Adaptation, Physiological, Conjugation, Genetic, MESH: Mosaicism, DNA, Bacterial, Transposable element, Molecular Sequence Data, Biology, MESH: Bacterial Proteins/genetics, MESH: Clostridium difficile/drug effects, MESH: Enterocolitis, Pseudomembranous/microbiology, MESH: DNA Transposable Elements/genetics, 03 medical and health sciences, Bacterial Proteins, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Virulence/genetics, MESH: Drug Resistance, Multiple, Bacterial/genetics, Gene, 030304 developmental biology, Whole genome sequencing, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Clostridioides difficile, 030306 microbiology, Microarray analysis techniques, MESH: Conjugation, Genetic, MESH: Adaptation, Physiological, MESH: DNA, Bacterial/genetics, Gastrointestinal Tract, MESH: Oligonucleotide Array Sequence Analysis, DNA Transposable Elements, Mobile genetic elements, MESH: Clostridium difficile/genetics, Genome, Bacterial
Abstract

International audience; We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.

Published
2006
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3. Genomics and genetics of Sulfolobus islandicus LAL14/1, a model hyperthermophilic archaeon

Author

Carole Jaubert, Jacques Oberto, Guennadi Sezonov, Diego Cortez, Mart Krupovic, Chloé Danioux, Qunxin She, Patrick Forterre, Ariane Bize, David Prangishvili, Biologie Moléculaire du Gène chez les Extrêmophiles (BMGE), Institut Pasteur [Paris], Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Hydrosystèmes et Bioprocédés (UR HBAN), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Danish Archaea Centre, Department of Biology [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Systématique, adaptation, évolution (SAE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by PhD fellowships from the ‘Ministère de l'enseignement supérieur et de la recherche’ (C.J. and C.D.) and by Pasteur-Weizmann (C.J.) allocations., We thank Nuno Peixeiro and Sophie Schbath for helpful discussions., Institut Pasteur [Paris] (IP), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Science [Copenhagen], and University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)

Subjects
MESH: Sequence Analysis, DNA, Genome, Genes, Archaeal, MESH: RNA, Transfer/metabolism, Plasmid, RNA, Transfer, CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats, genetics, MESH: Models, Genetic, Insertion sequence, MESH: Sulfolobus/genetics, crispr, MESH: Phylogeny, lcsh:QH301-705.5, Phylogeny, genome analysis, Genetics, 0303 health sciences, biology, General Neuroscience, MESH: Genomics, Genomics, MESH: Toxins, Biological/metabolism, Sulfolobus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: RNA, Transfer/genetics, MESH: Genes, Archaeal, Research Article, Gene Transfer, Horizontal, archaea, Immunology, Replication Origin, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: DNA Transposable Elements/genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, sulfolobus islandicus lal14/1, MESH: Replication Origin/genetics, Toxins, Biological, 030304 developmental biology, Models, Genetic, 030306 microbiology, Research, MESH: Antitoxins/metabolism, MESH: Clustered Regularly Interspaced Short Palindromic Repeats/genetics, Sequence Analysis, DNA, biology.organism_classification, MESH: Gene Transfer, Horizontal, SULFOLOBUS ISLANDICUS, lcsh:Biology (General), MESH: Sulfolobus/classification, DNA Transposable Elements, CRISPR Loci, Antitoxins, Mobile genetic elements, Rudivirus
Abstract

The 2 465 177 bp genome ofSulfolobus islandicusLAL14/1, host of the model rudivirus SIRV2, was sequenced. Exhaustive comparative genomic analysis ofS. islandicusLAL14/1 and the nine other completely sequencedS. islandicusstrains isolated from Iceland, Russia and USA revealed a highly syntenic common core genome of approximately 2 Mb and a long hyperplastic region containing most of the strain-specific genes. In LAL14/1, the latter region is enriched in insertion sequences, CRISPR (clustered regularly interspaced short palindromic repeats), glycosyl transferase genes, toxin–antitoxin genes and MITE (miniature inverted-repeat transposable elements). The tRNA genes of LAL14/1 are preferential targets for the integration of mobile elements but clusters of atypical genes (CAG) are also integrated elsewhere in the genome. LAL14/1 carries five CRISPR loci with 10 per cent of spacers matching perfectly or imperfectly the genomes of archaeal viruses and plasmids found in the Icelandic hot springs. Strikingly, the CRISPR_2 region of LAL14/1 carries an unusually long 1.9 kb spacer interspersed between two repeat regions and displays a high similarity to pING1-like conjugative plasmids. Finally, we have developed a genetic system forS. islandicusLAL14/1 and createdΔpyrEFandΔCRISPR_1mutants using double cross-over and pop-in/pop-out approaches, respectively. Thus, LAL14/1 is a promising model to study virus–host interactions and the CRISPR/Cas defence mechanism in Archaea.

Published
2013
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4. Silent Mischief: Bacteriophage Mu Insertions Contaminate Products of Escherichia coli Random Mutagenesis Performed Using Suicidal Transposon Delivery Plasmids Mobilized by Broad-Host-Range RP4 Conjugative Machinery

Author

Anne-Marie Guérout, Christophe Beloin, Lionel Ferrières, Didier Mazel, Toan Nham, Gaëlle Hémery, Jean-Marc Ghigo, Génétique des Biofilms, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Plasticité du Génome Bactérien (PGB), We thank Ariane Toussaint, Philippe Bouloc, and Jean-Claude Lazzaroni for critical reading of the manuscript. We are grateful to Frederique Leroux for providing plasmid pSC189-Cm and to many of our colleagues (Olivera Francetic, Mick Chandler, Romé Voulhoux, and Corinne Dorel) who provided us with SM10 and S17-1 derivative strains of various origins. L.F. is supported by grants from the European STREP 'NPARI' (LSHE-CT-2006-037692C.B), G.H. by grants from Saint-Gobain Re-cherche, and C.B. and J.-M.G. by grants from the Network of Excellence EuroPathoGenomics (LSHB-CT-2005-512061) and the ERA-NET Pathogenomics (ANR-06-PATHO-004-01), ANR-06-PATH-0004,EPS-MATRIX,Exploring protein secretionwithin the bacterial biofilm matrix(2006), European Project: 037692, European STREP 'NPARI', European Project: 512061,Network of Excellence EuroPathoGenomics, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA, Bacterial, Transposable element, MESH: Chromosomes, Bacterial, Mutant, Mutagenesis (molecular biology technique), Genetics and Molecular Biology, MESH: Escherichia coli/genetics, MESH: Mutagenesis, Insertional/methods, medicine.disease_cause, Microbiology, Bacteriophage mu, Bacteriophage, 03 medical and health sciences, MESH: Plasmids/genetics, MESH: DNA Transposable Elements/genetics, Plasmid, MESH: Bacteriophage mu/genetics, MESH: Bacteriophage mu/metabolism, Escherichia coli, medicine, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, biology, 030306 microbiology, Chromosome Mapping, MESH: Conjugation, Genetic, Chromosomes, Bacterial, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: DNA, Bacterial/genetics, Mutagenesis, Insertional, Conjugation, Genetic, DNA Transposable Elements, MESH: Escherichia coli/metabolism, Transposon mutagenesis, Bacteriophage Mu, MESH: Chromosome Mapping, Plasmids
Abstract

Random transposon mutagenesis is the strategy of choice for associating a phenotype with its unknown genetic determinants. It is generally performed by mobilization of a conditionally replicating vector delivering transposons to recipient cells using broad-host-range RP4 conjugative machinery carried by the donor strain. In the present study, we demonstrate that bacteriophage Mu, which was deliberately introduced during the original construction of the widely used donor strains SM10 λ pir and S17-1 λ pir , is silently transferred to Escherichia coli recipient cells at high frequency, both by hfr and by release of Mu particles by the donor strain. Our findings suggest that bacteriophage Mu could have contaminated many random-mutagenesis experiments performed on Mu-sensitive species with these popular donor strains, leading to potential misinterpretation of the transposon mutant phenotype and therefore perturbing analysis of mutant screens. To circumvent this problem, we precisely mapped Mu insertions in SM10 λ pir and S17-1 λ pir and constructed a new Mu-free donor strain, MFD pir , harboring stable hfr- deficient RP4 conjugative functions and sustaining replication of Π-dependent suicide vectors. This strain can therefore be used with most of the available transposon-delivering plasmids and should enable more efficient and easy-to-analyze mutant hunts in E. coli and other Mu-sensitive RP4 host bacteria.

Published
2010
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