Single Cell Multi-Omics Analysis of Chromothriptic Medulloblastoma Highlights Genomic and Transcriptomic Consequences of Genome Instability
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Efficacy and Mechanistic Evaluation of Tic10, a Novel Antitumor Agent
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Joshua Edward Allen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Oncology Commons Recommended Citation Allen, Joshua Edward, "Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent" (2012). Publicly Accessible Penn Dissertations. 488. https://repository.upenn.edu/edissertations/488 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/488 For more information, please contact [email protected]. Efficacy and Mechanisticv E aluation of Tic10, A Novel Antitumor Agent Abstract TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenous protein that selectively induces apoptosis in cancer cells and is a critical effector in the immune surveillance of cancer. Recombinant TRAIL and TRAIL-agonist antibodies are in clinical trials for the treatment of solid malignancies due to the cancer-specific cytotoxicity of TRAIL. Recombinant TRAIL has a short serum half-life and both recombinant TRAIL and TRAIL receptor agonist antibodies have a limited capacity to perfuse to tissue compartments such as the brain, limiting their efficacy in certain malignancies. To overcome such limitations, we searched for small molecules capable of inducing the TRAIL gene using a high throughput luciferase reporter gene assay. We selected TRAIL-inducing compound 10 (TIC10) for further study based on its induction of TRAIL at the cell surface and its promising therapeutic index. TIC10 is a potent, stable, and orally active antitumor agent that crosses the blood-brain barrier and transcriptionally induces TRAIL and TRAIL-mediated cell death in a p53-independent manner. -
Nucleolin and Its Role in Ribosomal Biogenesis
NUCLEOLIN: A NUCLEOLAR RNA-BINDING PROTEIN INVOLVED IN RIBOSOME BIOGENESIS Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Julia Fremerey aus Hamburg Düsseldorf, April 2016 2 Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. A. Borkhardt Korreferent: Prof. Dr. H. Schwender Tag der mündlichen Prüfung: 20.07.2016 3 Die vorgelegte Arbeit wurde von Juli 2012 bis März 2016 in der Klinik für Kinder- Onkologie, -Hämatologie und Klinische Immunologie des Universitätsklinikums Düsseldorf unter Anleitung von Prof. Dr. A. Borkhardt und in Kooperation mit dem ‚Laboratory of RNA Molecular Biology‘ an der Rockefeller Universität unter Anleitung von Prof. Dr. T. Tuschl angefertigt. 4 Dedicated to my family TABLE OF CONTENTS 5 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................... 5 LIST OF FIGURES ......................................................................................................10 LIST OF TABLES .......................................................................................................12 ABBREVIATION .........................................................................................................13 ABSTRACT ................................................................................................................19 ZUSAMMENFASSUNG -
Supp Material.Pdf
Simon et al. Supplementary information: Table of contents p.1 Supplementary material and methods p.2-4 • PoIy(I)-poly(C) Treatment • Flow Cytometry and Immunohistochemistry • Western Blotting • Quantitative RT-PCR • Fluorescence In Situ Hybridization • RNA-Seq • Exome capture • Sequencing Supplementary Figures and Tables Suppl. items Description pages Figure 1 Inactivation of Ezh2 affects normal thymocyte development 5 Figure 2 Ezh2 mouse leukemias express cell surface T cell receptor 6 Figure 3 Expression of EZH2 and Hox genes in T-ALL 7 Figure 4 Additional mutation et deletion of chromatin modifiers in T-ALL 8 Figure 5 PRC2 expression and activity in human lymphoproliferative disease 9 Figure 6 PRC2 regulatory network (String analysis) 10 Table 1 Primers and probes for detection of PRC2 genes 11 Table 2 Patient and T-ALL characteristics 12 Table 3 Statistics of RNA and DNA sequencing 13 Table 4 Mutations found in human T-ALLs (see Fig. 3D and Suppl. Fig. 4) 14 Table 5 SNP populations in analyzed human T-ALL samples 15 Table 6 List of altered genes in T-ALL for DAVID analysis 20 Table 7 List of David functional clusters 31 Table 8 List of acquired SNP tested in normal non leukemic DNA 32 1 Simon et al. Supplementary Material and Methods PoIy(I)-poly(C) Treatment. pIpC (GE Healthcare Lifesciences) was dissolved in endotoxin-free D-PBS (Gibco) at a concentration of 2 mg/ml. Mice received four consecutive injections of 150 μg pIpC every other day. The day of the last pIpC injection was designated as day 0 of experiment. -
Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. -
Supplementary Table 3: Genes Only Influenced By
Supplementary Table 3: Genes only influenced by X10 Illumina ID Gene ID Entrez Gene Name Fold change compared to vehicle 1810058M03RIK -1.104 2210008F06RIK 1.090 2310005E10RIK -1.175 2610016F04RIK 1.081 2610029K11RIK 1.130 381484 Gm5150 predicted gene 5150 -1.230 4833425P12RIK -1.127 4933412E12RIK -1.333 6030458P06RIK -1.131 6430550H21RIK 1.073 6530401D06RIK 1.229 9030607L17RIK -1.122 A330043C08RIK 1.113 A330043L12 1.054 A530092L01RIK -1.069 A630054D14 1.072 A630097D09RIK -1.102 AA409316 FAM83H family with sequence similarity 83, member H 1.142 AAAS AAAS achalasia, adrenocortical insufficiency, alacrimia 1.144 ACADL ACADL acyl-CoA dehydrogenase, long chain -1.135 ACOT1 ACOT1 acyl-CoA thioesterase 1 -1.191 ADAMTSL5 ADAMTSL5 ADAMTS-like 5 1.210 AFG3L2 AFG3L2 AFG3 ATPase family gene 3-like 2 (S. cerevisiae) 1.212 AI256775 RFESD Rieske (Fe-S) domain containing 1.134 Lipo1 (includes AI747699 others) lipase, member O2 -1.083 AKAP8L AKAP8L A kinase (PRKA) anchor protein 8-like -1.263 AKR7A5 -1.225 AMBP AMBP alpha-1-microglobulin/bikunin precursor 1.074 ANAPC2 ANAPC2 anaphase promoting complex subunit 2 -1.134 ANKRD1 ANKRD1 ankyrin repeat domain 1 (cardiac muscle) 1.314 APOA1 APOA1 apolipoprotein A-I -1.086 ARHGAP26 ARHGAP26 Rho GTPase activating protein 26 -1.083 ARL5A ARL5A ADP-ribosylation factor-like 5A -1.212 ARMC3 ARMC3 armadillo repeat containing 3 -1.077 ARPC5 ARPC5 actin related protein 2/3 complex, subunit 5, 16kDa -1.190 activating transcription factor 4 (tax-responsive enhancer element ATF4 ATF4 B67) 1.481 AU014645 NCBP1 nuclear cap -
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Ki-67 (ABT-KI67) mouse mAb Ready to use Catalog No : YM6189R Reactivity : Human, Mouse Applications : IHC-p,IF/ICC Gene Name : MKI67 Protein Name : Antigen KI-67 Human Gene Id : 4288 Human Swiss Prot P46013 No : Immunogen : Synthesized peptide derived from human Ki-67 Specificity : This antibody detects endogenous levels of human Ki-67. Heat-induced epitope retrieval (HIER) TRIS-EDTA of pH8.0 was highly recommended as antigen repair method in paraffin section Formulation : Liquid in PBS containing, 0.5% BSA and 0.02% sodium azide. Source : Mouse/IgG1, Kappa Dilution : Ready to use for IHC-p and IF Purification : The antibody was affinity-purified from mouse ascites by affinity- chromatography using specific immunogen. Storage Stability : 4°C/ 1 years Background : marker of proliferation Ki-67(MKI67) Homo sapiens This gene encodes a nuclear protein that is associated with and may be necessary for cellular proliferation. Alternatively spliced transcript variants have been described. A related pseudogene exists on chromosome X. [provided by RefSeq, Mar 2009], Function : developmental stage:Expression of this antigen occurs preferentially during late G1, S, G2 and M phases of the cell cycle, while in cells in G0 phase the antigen cannot be detected.,function:Thought to be required for maintaining cell 1 / 2 proliferation.,online information:Ki-67 entry,similarity:Contains 1 FHA domain.,subcellular location:Predominantly localized in the G1 phase in the perinucleolar region, in the later phases it is also detected throughout the nuclear interior, being predominantly localized in the nuclear matrix. In mitosis, it is present on all chromosomes.,subunit:Interacts with KIF15. -
UC San Diego UC San Diego Previously Published Works
UC San Diego UC San Diego Previously Published Works Title The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation. Permalink https://escholarship.org/uc/item/8645k8vd Journal eLife, 5(MARCH2016) ISSN 2050-084X Authors Lin, Tsung-Chieh Su, Chia-Yi Wu, Pei-Yu et al. Publication Date 2016-03-17 DOI 10.7554/elife.11288 Peer reviewed eScholarship.org Powered by the California Digital Library University of California RESEARCH ARTICLE The nucleolar protein NIFK promotes cancer progression via CK1a/b-catenin in metastasis and Ki-67-dependent cell proliferation Tsung-Chieh Lin1†, Chia-Yi Su1†, Pei-Yu Wu2, Tsung-Ching Lai1, Wen-An Pan2,3, Yi-Hua Jan1, Yu-Chang Chang1, Chi-Tai Yeh4, Chi-Long Chen5,6, Luo-Ping Ger7, Hong-Tai Chang8,9, Chih-Jen Yang10, Ming-Shyan Huang10, Yu-Peng Liu11,12, Yuan-Feng Lin13, John Y-J Shyy14, Ming-Daw Tsai1,2*, Michael Hsiao1* 1Genomics Research Center, Academia Sinica, Taipei, Taiwan; 2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; 3Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan; 4Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; 5Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; 6Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan; 7Department of Medical Education and Research, Kaohsiung Veterans General, Kaohsiung, Taiwan; 8Department of Surgery, -
Genome-Wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells
Journal of Visualized Experiments www.jove.com Video Article Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells Henrik D. Møller1, Rasmus K. Bojsen2, Chris Tachibana3, Lance Parsons4, David Botstein5, Birgitte Regenberg1 1 Department of Biology, University of Copenhagen 2 National Veterinary Institute, Technical University of Denmark 3 Group Health Research Institute 4 Lewis-Sigler Institute for Integrative Genomics, Princeton University 5 Calico Life Sciences LLC Correspondence to: Birgitte Regenberg at [email protected] URL: https://www.jove.com/video/54239 DOI: doi:10.3791/54239 Keywords: Molecular Biology, Issue 110, Circle-Seq, deletion, eccDNA, rDNA, ERC, ECE, microDNA, minichromosomes, small polydispersed circular DNA, spcDNA, double minute, amplification Date Published: 4/4/2016 Citation: Møller, H.D., Bojsen, R.K., Tachibana, C., Parsons, L., Botstein, D., Regenberg, B. Genome-wide Purification of Extrachromosomal Circular DNA from Eukaryotic Cells. J. Vis. Exp. (110), e54239, doi:10.3791/54239 (2016). Abstract Extrachromosomal circular DNAs (eccDNAs) are common genetic elements in Saccharomyces cerevisiae and are reported in other eukaryotes as well. EccDNAs contribute to genetic variation among somatic cells in multicellular organisms and to evolution of unicellular eukaryotes. Sensitive methods for detecting eccDNA are needed to clarify how these elements affect genome stability and how environmental and biological factors induce their formation in eukaryotic cells. This video presents a sensitive eccDNA-purification method called Circle-Seq. The method encompasses column purification of circular DNA, removal of remaining linear chromosomal DNA, rolling-circle amplification of eccDNA, deep sequencing, and mapping. Extensive exonuclease treatment was required for sufficient linear chromosomal DNA degradation. The rolling-circle amplification step by φ29 polymerase enriched for circular DNA over linear DNA. -
Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
Published OnlineFirst August 12, 2013; DOI: 10.1158/0008-5472.CAN-13-0186 Cancer Tumor and Stem Cell Biology Research Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons J. Zachary Sanborn1,2,Sofie R. Salama2,3, Mia Grifford2, Cameron W. Brennan4, Tom Mikkelsen6, Suresh Jhanwar5, Sol Katzman2, Lynda Chin7, and David Haussler2,3 Abstract DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrange- ments and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. -
A Acentric Fragment Linear One Telomere Radiation One Broken End Endonuclease Break-Inducing Mutagen
Chromosome Res https://doi.org/10.1007/s10577-020-09636-z REVIEW Mechanisms driving acentric chromosome transmission Brandt Warecki & William Sullivan Received: 2 June 2020 /Revised: 16 July 2020 /Accepted: 19 July 2020 # Springer Nature B.V. 2020 Abstract The kinetochore-microtubule association is a Keywords Acentric . chromosome fragment . mitosis . core, conserved event that drives chromosome transmis- microtubules . double minutes . genome stability sion during mitosis. Failure to establish this association on even a single chromosome results in aneuploidy Abbreviations leading to cell death or the development of cancer. APC/C Anaphase-promoting complex However, although many chromosomes lacking centro- PtK cells Potorous tridactylus cells meres, termed acentrics, fail to segregate, studies in a UFBs Ultrafine DNA bridges number of systems reveal robust alternative mecha- CHMP4C Charged multivesicular body nisms that can drive segregation and successful pole- protein 4C ward transport of acentrics. In contrast to the canonical ESCRT-III Endosomal sorting complexes mechanism that relies on end-on microtubule attach- required for transport-III ments to kinetochores, mechanisms of acentric trans- mission largely fall into three categories: direct attach- ments to other chromosomes, kinetochore-independent lateral attachments to microtubules, and long-range teth- er-based attachments. Here, we review these “non-ca- Kinetochore-microtubule interactions drive nonical” methods of acentric chromosome transmission. poleward chromosome transmission Just as the discovery and exploration of cell cycle checkpoints provided insight into both the origins of In order to produce genetically identical daughter cells cancer and new therapies, identifying mechanisms and following mitosis, a cell must first duplicate its genome structures specifically involved in acentric segregation and then equally partition genetic material to its daugh- may have a significant impact on basic and applied ter cells through chromatid segregation. -
Hyper Telomere Recombination Accelerates Replicative Senescence and May Promote Premature Aging
Hyper telomere recombination accelerates replicative senescence and may promote premature aging R. Tanner Hagelstroma,b, Krastan B. Blagoevc,d, Laura J. Niedernhofere, Edwin H. Goodwinf, and Susan M. Baileya,1 aDepartment of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1618; bPharmaceutical Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004; cNational Science Foundation, Arlington, VA 22230; dDepartment of Physics Cavendish Laboratory, Cambridge University, Cambridge CB3 0HE, United Kingdom; eDepartment of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine and Cancer Institute, Pittsburgh, PA 15261; and fKromaTiD Inc., Fort Collins, CO 80524 Edited* by José N. Onuchic, University of California San Diego, La Jolla, CA, and approved August 3, 2010 (received for review May 7, 2010) Werner syndrome and Bloom syndrome result from defects in the cell-cycle arrest known as senescence (12). Most human tissues lack RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and sufficient telomerase activity to maintain telomere length through- display premature aging phenotypes. Similarly, XFE progeroid out life, limiting cell division potential. The majority of cancers syndrome results from defects in the ERCC1-XPF DNA repair endo- circumvent this tumor-suppressor mechanism by reactivating telo- nuclease. To gain insight into the origin of cellular senescence and merase (13), thus removing telomere shortening as a barrier to human aging, we analyzed the dependence of sister chromatid continuous proliferation. In some situations, a recombination- exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telo- based mechanism known as “alternative lengthening of telomeres” meric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, (ALT) maintains telomere length in the absence of telomerase (14). -
Discordant Inheritance of Chromosomal and Extrachromosomal DNA Elements 2 Contributes to Dynamic Disease Evolution in Glioblastoma
bioRxiv preprint doi: https://doi.org/10.1101/081158; this version posted June 27, 2017. 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. 1 Discordant inheritance of chromosomal and extrachromosomal DNA elements 2 contributes to dynamic disease evolution in glioblastoma 3 Ana C. deCarvalho1*†, Hoon Kim2*, Laila M. Poisson3, Mary E. Winn4, Claudius 4 Mueller5, David Cherba4, Julie Koeman6, Sahil Seth7, Alexei Protopopov7, Michelle 5 Felicella8, Siyuan Zheng9, Asha Multani10, Yongying Jiang7, Jianhua Zhang7, Do-Hyun 6 Nam11, 12, 13 Emanuel F. Petricoin5, Lynda Chin2, 7, Tom Mikkelsen1, 14†, Roel G.W. 7 Verhaak2† 8 9 1Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA. 10 2The Jackson Laboratory for Genomic Medicine, Farmington, CT 06130, USA. 11 3Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202, USA. 12 4Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 13 49503, USA. 14 5Center for Applied Proteomics and Personalized Medicine, George Mason University, 15 Manassas, VA, USA 16 6Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 17 49503, USA. 18 7Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer 19 Center, Houston, TX 77030, USA. 20 8Department of Pathology, Henry Ford Hospital, Detroit, MI 48202, USA. 21 9Deptartment of Genetics, The University of Texas MD Anderson Cancer Center, 22 Houston,