A Gene Expression Signature Identifying Transient DNMT1
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Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma
cancers Article Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma 1, 1, 1 1 1 Lan Wang y, Anudeep Yekula y, Koushik Muralidharan , Julia L. Small , Zachary S. Rosh , Keiko M. Kang 1,2, Bob S. Carter 1,* and Leonora Balaj 1,* 1 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; [email protected] (L.W.); [email protected] (A.Y.); [email protected] (K.M.); [email protected] (J.L.S.); [email protected] (Z.S.R.); [email protected] (K.M.K.) 2 School of Medicine, University of California San Diego, San Diego, CA 92092, USA * Correspondence: [email protected] (B.S.C.); [email protected] (L.B.) These authors contributed equally. y Received: 11 March 2020; Accepted: 7 May 2020; Published: 13 May 2020 Abstract: Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids. Here, we used targeted RNA sequencing to screen GBM tissue and the matched plasma of patients (n = 9) for RNA fusion transcripts. We identified two novel fusion transcripts in GBM tissue and five novel fusions in the matched plasma of GBM patients. The fusion transcripts FGFR3-TACC3 and VTI1A-TCF7L2 were detected in both tissue and matched plasma. -
Expression of Cancer-Testis Antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in Myxoid and Round Cell Liposarcoma
Modern Pathology (2014) 27, 1238–1245 1238 & 2014 USCAP, Inc All rights reserved 0893-3952/14 $32.00 Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma Jessica A Hemminger1, Amanda Ewart Toland2, Thomas J Scharschmidt3, Joel L Mayerson3, Denis C Guttridge2 and O Hans Iwenofu1 1Department of Pathology and Laboratory Medicine, Wexner Medical Center at The Ohio State University, Columbus, OH, USA; 2Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA and 3Department of Orthopedics, The Ohio State University Wexner Medical Center, Columbus, OH, USA Myxoid and round-cell liposarcoma is a frequently encountered liposarcoma subtype. The mainstay of treatment remains surgical excision with or without chemoradiation. However, treatment options are limited in the setting of metastatic disease. Cancer-testis antigens are immunogenic antigens with the expression largely restricted to testicular germ cells and various malignancies, making them attractive targets for cancer immunotherapy. Gene expression studies have reported the expression of various cancer-testis antigens in liposarcoma, with mRNA expression of CTAG1B, CTAG2, MAGEA9, and PRAME described specifically in myxoid and round-cell liposarcoma. Herein, we further explore the expression of the cancer-testis antigens MAGEA1, ACRBP, PRAME, and SSX2 in myxoid and round-cell liposarcoma by immunohistochemistry in addition to determining mRNA levels of CTAG2 (LAGE-1), PRAME, and MAGEA3 by quantitative real-time PCR. Samples in formalin-fixed paraffin-embedded blocks (n ¼ 37) and frozen tissue (n ¼ 8) were obtained for immunohistochemistry and quantitative real-time PCR, respectively. Full sections were stained with antibodies to MAGEA1, ACRBP, PRAME, and SSX2 and staining was assessed for intensity (1–2 þ ) and percent tumor positivity. -
Primate Specific Retrotransposons, Svas, in the Evolution of Networks That Alter Brain Function
Title: Primate specific retrotransposons, SVAs, in the evolution of networks that alter brain function. Olga Vasieva1*, Sultan Cetiner1, Abigail Savage2, Gerald G. Schumann3, Vivien J Bubb2, John P Quinn2*, 1 Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, U.K 2 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK 3 Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, D-63225 Germany *. Corresponding author Olga Vasieva: Institute of Integrative Biology, Department of Comparative genomics, University of Liverpool, Liverpool, L69 7ZB, [email protected] ; Tel: (+44) 151 795 4456; FAX:(+44) 151 795 4406 John Quinn: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK, [email protected]; Tel: (+44) 151 794 5498. Key words: SVA, trans-mobilisation, behaviour, brain, evolution, psychiatric disorders 1 Abstract The hominid-specific non-LTR retrotransposon termed SINE–VNTR–Alu (SVA) is the youngest of the transposable elements in the human genome. The propagation of the most ancient SVA type A took place about 13.5 Myrs ago, and the youngest SVA types appeared in the human genome after the chimpanzee divergence. Functional enrichment analysis of genes associated with SVA insertions demonstrated their strong link to multiple ontological categories attributed to brain function and the disorders. SVA types that expanded their presence in the human genome at different stages of hominoid life history were also associated with progressively evolving behavioural features that indicated a potential impact of SVA propagation on a cognitive ability of a modern human. -
Multiple Myeloma Risk Variant at 7P15.3 Creates an IRF4-Binding Site and Interferes with CDCA7L Expression
ARTICLE Received 7 Jul 2016 | Accepted 19 Oct 2016 | Published 24 Nov 2016 DOI: 10.1038/ncomms13656 OPEN Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression Ni Li1,2, David C. Johnson2, Niels Weinhold3,4, James B. Studd1, Giulia Orlando1, Fabio Mirabella2, Jonathan S. Mitchell1, Tobias Meissner5, Martin Kaiser2, Hartmut Goldschmidt4,6, Kari Hemminki7,8, Gareth J. Morgan3 & Richard S. Houlston1,2 Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G4T, the most highly associated variant (P ¼ 5.30 Â 10 À 25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P ¼ 1.95 Â 10 À 36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM. 1 Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK. 2 Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK. 3 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. 4 Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany. -
WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). -
This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Investigation into the role of LSH ATPase in chromatin remodelling Alina Gukova Doctor of Philosophy – University of Edinburgh – 2020 ABSTRACT Chromatin remodelling is a crucial nuclear process affecting replication, transcription and repair. Global reduction of DNA methylation is observed in Immunodeficiency-Centromeric Instability-Facial Anomaly (ICF) syndrome. Several proteins were found to be mutated in patients diagnosed with ICF, among them are LSH and CDCA7. LSH is a chromatin remodeller bearing homology to the members of Sf2 remodelling family. A point mutation in its ATPase lobe was identified in ICF. CDCA7 is a zinc finger protein that was recently found to be crucial for nucleosome remodelling activity of LSH. Several point mutations in its zinc finger domain were described in ICF patients. In vitro and in vivo studies have shown that LSH-/- phenotype demonstrates reduction of global DNA methylation, implying that chromatin remodelling LSH functions may be required for the efficient methyltransferase activity, linking this finding to ICF phenotype. -
Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster
International Journal of Environmental Research and Public Health Article Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster Alan A. Arslan 1,2,3,* , Stephanie Tuminello 2, Lei Yang 2, Yian Zhang 2, Nedim Durmus 4, Matija Snuderl 5, Adriana Heguy 5,6, Anne Zeleniuch-Jacquotte 2,3, Yongzhao Shao 2,3 and Joan Reibman 4 1 Department of Obstetrics and Gynecology, New York University Langone Health, New York, NY 10016, USA 2 Department of Population Health, New York University Langone Health, New York, NY 10016, USA; [email protected] (S.T.); [email protected] (L.Y.); [email protected] (Y.Z.); [email protected] (A.Z.-J.); [email protected] (Y.S.) 3 NYU Perlmutter Comprehensive Cancer Center, New York, NY 10016, USA 4 Department of Medicine, New York University Langone Health, New York, NY 10016, USA; [email protected] (N.D.); [email protected] (J.R.) 5 Department of Pathology, New York University Langone Health, New York, NY 10016, USA; [email protected] (M.S.); [email protected] (A.H.) 6 NYU Langone’s Genome Technology Center, New York, NY 10016, USA * Correspondence: [email protected] Received: 30 June 2020; Accepted: 25 July 2020; Published: 30 July 2020 Abstract: The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. -
Genome-Wide Analysis of Cancer/Testis Gene Expression
Genome-wide analysis of cancer/testis gene expression Oliver Hofmanna,b,1, Otavia L. Caballeroc, Brian J. Stevensond,e, Yao-Tseng Chenf, Tzeela Cohenc, Ramon Chuac, Christopher A. Maherb, Sumir Panjib, Ulf Schaeferb, Adele Krugerb, Minna Lehvaslaihob, Piero Carnincig,h, Yoshihide Hayashizakig,h, C. Victor Jongeneeld,e, Andrew J. G. Simpsonc, Lloyd J. Oldc,1, and Winston Hidea,b aDepartment of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, SPH2, 4th Floor, Boston, MA 02115; bSouth African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; cLudwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; dLudwig Institute for Cancer Research, Lausanne Branch, 1015 Lausanne, Switzerland; eSwiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; fWeill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021; gGenome Exploration Research Group (Genome Network Project Core Group), RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; and hGenome Science Laboratory, Discovery Research Institute, RIKEN Wako Institute, 2-1 Hirosawa, Wako, Saitama, 3510198, Japan Contributed by Lloyd J. Old, October 28, 2008 (sent for review June 6, 2008) Cancer/Testis (CT) genes, normally expressed in germ line cells but expression profile information frequently limited to the original also activated in a wide range of cancer types, often encode defining articles. In some cases, e.g., ACRBP, the original antigens that are immunogenic in cancer patients, and present CT-restricted expression in normal tissues could not be con- potential for use as biomarkers and targets for immunotherapy. -
In-Silico Discovery of Cancer-Specific Peptide-HLA Complexes for Targeted Therapy Ankur Dhanik*, Jessica R
Dhanik et al. BMC Bioinformatics (2016) 17:286 DOI 10.1186/s12859-016-1150-2 RESEARCH ARTICLE Open Access In-silico discovery of cancer-specific peptide-HLA complexes for targeted therapy Ankur Dhanik*, Jessica R. Kirshner, Douglas MacDonald, Gavin Thurston, Hsin C. Lin, Andrew J. Murphy and Wen Zhang Abstract Background: Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) Class I molecules bind to peptide fragments of proteins degraded inside the cell and display them on the cell surface. We are interested in peptide-HLA complexes involving peptides that are derived from proteins specifically expressed in cancer cells. Such complexes have been shown to provide an effective means of precisely targeting cancer cells by engineered T-cells and antibodies, which would be an improvement over current chemotherapeutic agents that indiscriminately kill proliferating cells. An important concern with the targeting of peptide-HLA complexes is off-target toxicity that could occur due to the presence of complexes similar to the target complex in cells from essential, normal tissues. Results: We developed a novel computational strategy for identifying potential peptide-HLA cancer targets and evaluating the likelihood of off-target toxicity associated with these targets. Our strategy combines sequence-based and structure-based approaches in a unique way to predict potential off-targets. The focus of our work is on the complexes involving the most frequent HLA class I allele HLA-A*02:01. Using our strategy, we predicted the off-target toxicity observed in past clinical trials. We employed it to perform a first-ever comprehensive exploration of the human peptidome to identify cancer-specific targets utilizing gene expression data from TCGA (The Cancer Genome Atlas) and GTEx (Gene Tissue Expression), and structural data from PDB (Protein Data Bank). -
Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-Cov-2
Resource Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 Graphical Abstract Authors Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, ..., Andrew A. Wilson, Elke Muhlberger,€ Andrew Emili Correspondence [email protected] (D.N.K.), [email protected] (A.A.W.), [email protected] (E.M.), [email protected] (A.E.) In Brief Hekman et al. describe how a layer of primary stem cells (iAT2s) recapitulating lung biology responds to infection with SARS-CoV-2. They compare their work to previous studies with immortalized cell lines. Their data predict what effect the virus has on a lung cell and which drugs may slow infection. Highlights d SARS-CoV-2 infection in induced lung cells is characterized by phosphoproteomics d Analysis of response reveals host cell signaling and protein expression profile d Comparison to studies in undifferentiated cell lines shows unique pathology in iAT2s d Systems-level predictions find druggable pathways that can impede viral life cycle Hekman et al., 2020, Molecular Cell 80, 1–19 December 17, 2020 ª 2020 Elsevier Inc. https://doi.org/10.1016/j.molcel.2020.11.028 ll Please cite this article in press as: Hekman et al., Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2, Mo- lecular Cell (2020), https://doi.org/10.1016/j.molcel.2020.11.028 ll Resource Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 Ryan M. Hekman,1,2,23 Adam J. Hume,3,4,23 Raghuveera Kumar Goel,1,2,23 Kristine M. -
A Novel Protein-DNA Interaction Involved with the Cpg Dinucleotide At
ARTICLECell Research, 14 (4), Aug 2004 Cell Research (2004); Jie 14 ZHANG (4):283-294 et al http://www.cell-research.com A novel protein-DNA interaction involved with the CpG dinucleotide at -30 upstream is linked to the DNA methylation mediated transcription silencing of the MAGE-A1 gene Jie ZHANG, Jian YU, Jun GU, Bao Mei GAO, Ying Jun ZHAO, Peng WANG, Hong Yu ZHANG, Jing De ZHU* The State-key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, LN 2200/25, Xietu Road, Shanghai 200032, China. ABSTRACT To understand the DNA-methylation mediated gene silencing mechanisms, we analyzed in cell culture of the pro- moter function of the MAGE-A1 gene, which is frequently demethylated and over-expressed in human hepatocellular carcinoma. We have established the correlation of the DNA methylation of the promoter CpG island with expression status of this gene in a panel of the established liver cancer cell lines. The crucial CpG dinucleotide(s) within the minimal promoter subjected to the control mediated by DNA methylation with profound biological functions was also delineated. Furthermore, a novel sequence-specific DNA-protein interaction at the -30 CpG dinucleotide upstream of the gene was found having a vital part to play in the DNA methylation mediated transcription silencing of the MAGE-A1 gene. Our results would not only provide new insights into the DNA methylation mediated mechanisms over transcription of the MAGE-A1 gene, but also pave the way for further defining the cross-talk among DNA methylation, histone modifica- tion and chromatin remodeling in detail. -
(MAGEA1) (NM 004988) Human Tagged ORF Clone Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC202134 MAGE 1 (MAGEA1) (NM_004988) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: MAGE 1 (MAGEA1) (NM_004988) Human Tagged ORF Clone Tag: Myc-DDK Symbol: MAGEA1 Synonyms: CT1.1; MAGE1 Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin ORF Nucleotide >RC202134 ORF sequence Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGTCTCTTGAGCAGAGGAGTCTGCACTGCAAGCCTGAGGAAGCCCTTGAGGCCCAACAAGAGGCCCTGG GCCTGGTGTGTGTGCAGGCTGCCGCCTCCTCCTCCTCTCCTCTGGTCCTGGGCACCCTGGAGGAGGTGCC CACTGCTGGGTCAACAGATCCTCCCCAGAGTCCTCAGGGAGCCTCCGCCTTTCCCACTACCATCAACTTC ACTCGACAGAGGCAACCCAGTGAGGGTTCCAGCAGCCGTGAAGAGGAGGGGCCAAGCACCTCTTGTATCC TGGAGTCCTTGTTCCGAGCAGTAATCACTAAGAAGGTGGCTGATTTGGTTGGTTTTCTGCTCCTCAAATA TCGAGCCAGGGAGCCAGTCACAAAGGCAGAAATGCTGGAGAGTGTCATCAAAAATTACAAGCACTGTTTT CCTGAGATCTTCGGCAAAGCCTCTGAGTCCTTGCAGCTGGTCTTTGGCATTGACGTGAAGGAAGCAGACC CCACCGGCCACTCCTATGTCCTTGTCACCTGCCTAGGTCTCTCCTATGATGGCCTGCTGGGTGATAATCA GATCATGCCCAAGACAGGCTTCCTGATAATTGTCCTGGTCATGATTGCAATGGAGGGCGGCCATGCTCCT GAGGAGGAAATCTGGGAGGAGCTGAGTGTGATGGAGGTGTATGATGGGAGGGAGCACAGTGCCTATGGGG AGCCCAGGAAGCTGCTCACCCAAGATTTGGTGCAGGAAAAGTACCTGGAGTACCGGCAGGTGCCGGACAG TGATCCCGCACGCTATGAGTTCCTGTGGGGTCCAAGGGCCCTTGCTGAAACCAGCTATGTGAAAGTCCTT GAGTATGTGATCAAGGTCAGTGCAAGAGTTCGCTTTTTCTTCCCATCCCTGCGTGAAGCAGCTTTGAGAG