Genome-Wide Identification of Genes Regulating DNA Methylation Using Genetic Anchors for Causal Inference
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University of California, San Diego
UNIVERSITY OF CALIFORNIA, SAN DIEGO The post-terminal differentiation fate of RNAs revealed by next-generation sequencing A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Gloria Kuo Lefkowitz Committee in Charge: Professor Benjamin D. Yu, Chair Professor Richard Gallo Professor Bruce A. Hamilton Professor Miles F. Wilkinson Professor Eugene Yeo 2012 Copyright Gloria Kuo Lefkowitz, 2012 All rights reserved. The Dissertation of Gloria Kuo Lefkowitz is approved, and it is acceptable in quality and form for publication on microfilm and electronically: __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ Chair University of California, San Diego 2012 iii DEDICATION Ma and Ba, for your early indulgence and support. Matt and James, for choosing more practical callings. Roy, my love, for patiently sharing the ups and downs of this journey. iv EPIGRAPH It is foolish to tear one's hair in grief, as though sorrow would be made less by baldness. ~Cicero v TABLE OF CONTENTS Signature Page .............................................................................................................. iii Dedication .................................................................................................................... -
Global-Scale Analysis of the Dynamic Transcriptional Adaptations Within Skeletal Muscle During Hypertrophic Growth
University of Kentucky UKnowledge Theses and Dissertations--Physiology Physiology 2015 GLOBAL-SCALE ANALYSIS OF THE DYNAMIC TRANSCRIPTIONAL ADAPTATIONS WITHIN SKELETAL MUSCLE DURING HYPERTROPHIC GROWTH Tyler Kirby University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Kirby, Tyler, "GLOBAL-SCALE ANALYSIS OF THE DYNAMIC TRANSCRIPTIONAL ADAPTATIONS WITHIN SKELETAL MUSCLE DURING HYPERTROPHIC GROWTH" (2015). Theses and Dissertations--Physiology. 22. https://uknowledge.uky.edu/physiology_etds/22 This Doctoral Dissertation is brought to you for free and open access by the Physiology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Physiology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. -
CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding Mandy Muller, Caroline Demeret
CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding Mandy Muller, Caroline Demeret To cite this version: Mandy Muller, Caroline Demeret. CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding. PLoS ONE, Public Library of Science, 2014, 9 (3), pp.e92581. 10.1371/journal.pone.0092581. pasteur-01971541 HAL Id: pasteur-01971541 https://hal-pasteur.archives-ouvertes.fr/pasteur-01971541 Submitted on 7 Jan 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License CCHCR1 Interacts Specifically with the E2 Protein of Human Papillomavirus Type 16 on a Surface Overlapping BRD4 Binding Mandy Muller1,2¤b, Caroline Demeret1*¤a 1 Unite´ Ge´ne´tique Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France, 2 Universite´ Paris Diderot, Sorbonne Paris Cite´, Cellule Pasteur, Paris, France Abstract The Human Papillomavirus E2 proteins are key regulators of the viral life cycle, whose functions are commonly mediated through protein-protein interactions with the host cell proteome. We identified an interaction between E2 and a cellular protein called CCHCR1, which proved highly specific for the HPV16 genotype, the most prevalent in HPV-associated cancers. -
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. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
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Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/) -
Genomic Analyses of PMBL Reveal New Drivers and Mechanisms of Sensitivity to PD-1 Blockade
Regular Article LYMPHOID NEOPLASIA Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade Bjoern Chapuy,1,2,* Chip Stewart,3,* Andrew J. Dunford,3,* Jaegil Kim,3 Kirsty Wienand,1 Atanas Kamburov,3 Gabriel K. Griffin,4 Pei-Hsuan Chen,4 Ana Lako,4 Robert A. Redd,5 Claire M. Cote,1 Matthew D. Ducar,6 Aaron R. Thorner,6 Scott J. Rodig,4 Gad Getz,3,7,8,† Downloaded from https://ashpublications.org/blood/article-pdf/134/26/2369/1549702/bloodbld2019002067.pdf by Margaret Shipp on 30 December 2019 and Margaret A. Shipp1,† 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2Department of Hematology and Oncology, University Medical Center Gottingen,¨ Gottingen,¨ Germany; 3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; 4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 5Department of Data Sciences and 6Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA; and 7Department of Pathology and 8Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA KEY POINTS Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, l Comprehensive genomic analyses of and molecular features with classical Hodgkin lymphoma (cHL), including constitutive PMBL reveal new activation of nuclear factor kB (NF-kB), JAK/STAT signaling, and programmed cell death genetic drivers such protein 1 (PD-1)–mediated immune evasion. The demonstrated efficacy of PD-1 blockade in as ZNF217. relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration l High mutational and underscored the importance of characterizing targetable genetic vulnerabilities in this burden, MSI, and disease. -
Transcriptome Analysis of Human Diabetic Kidney Disease
ORIGINAL ARTICLE Transcriptome Analysis of Human Diabetic Kidney Disease Karolina I. Woroniecka,1 Ae Seo Deok Park,1 Davoud Mohtat,2 David B. Thomas,3 James M. Pullman,4 and Katalin Susztak1,5 OBJECTIVE—Diabetic kidney disease (DKD) is the single cases, mild and then moderate mesangial expansion can be leading cause of kidney failure in the U.S., for which a cure has observed. In general, diabetic kidney disease (DKD) is not yet been found. The aim of our study was to provide an considered a nonimmune-mediated degenerative disease unbiased catalog of gene-expression changes in human diabetic of the glomerulus; however, it has long been noted that kidney biopsy samples. complement and immunoglobulins sometimes can be de- — tected in diseased glomeruli, although their role and sig- RESEARCH DESIGN AND METHODS Affymetrix expression fi arrays were used to identify differentially regulated transcripts in ni cance is not clear (4). 44 microdissected human kidney samples. The DKD samples were The understanding of DKD has been challenged by multi- significant for their racial diversity and decreased glomerular ple issues. First, the diagnosis of DKD usually is made using filtration rate (~20–30 mL/min). Stringent statistical analysis, using clinical criteria, and kidney biopsy often is not performed. the Benjamini-Hochberg corrected two-tailed t test, was used to According to current clinical practice, the development of identify differentially expressed transcripts in control and diseased albuminuria in patients with diabetes is sufficient to make the glomeruli and tubuli. Two different Web-based algorithms were fi diagnosis of DKD (5). We do not understand the correlation used to de ne differentially regulated pathways. -
The Pluripotent Regulatory Circuitry Connecting Promoters to Their Long-Range Interacting Elements
Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Resource The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements Stefan Schoenfelder,1,9 Mayra Furlan-Magaril,1,9 Borbala Mifsud,2,3,9 Filipe Tavares-Cadete,2,3,9 Robert Sugar,3,4 Biola-Maria Javierre,1 Takashi Nagano,1 Yulia Katsman,5 Moorthy Sakthidevi,5 Steven W. Wingett,1,6 Emilia Dimitrova,1 Andrew Dimond,1 Lucas B. Edelman,1 Sarah Elderkin,1 Kristina Tabbada,1 Elodie Darbo,2,3 Simon Andrews,6 Bram Herman,7 Andy Higgs,7 Emily LeProust,7 Cameron S. Osborne,1 Jennifer A. Mitchell,5 Nicholas M. Luscombe,2,3,8 and Peter Fraser1 1Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom; 2University College London, UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom; 3Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom; 4EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom; 5Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada; 6Bioinformatics Group, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom; 7Agilent Technologies, Inc., Santa Clara, California 95051, USA; 8Okinawa Institute for Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa 904-0495, Japan The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. -
Supporting Information
Supporting Information Mor and Cohen 10.1073/pnas.1215722110 SI Methods containing primer and 5 μL of cDNA. PCR amplification was Gene Array Experiments. Human CD4 T cells were isolated as preceded by incubation of the mixture for 10 min at 95 °C, and described, and incubated in 24-well plates (Nunc), 4 × 106 cells/ the amplification step consisted of 45 cycles of denaturation, mL with plate-bound anti-human CD3 (OKT3) at 2 μg/mL. The annealing, and extension. Denaturation was performed for 15 s stimulation was performed in RPMI medium supplemented with at 95 °C; annealing was performed in 60 °C; and the extension 0.1% BSA. After 2 h of stimulation with or without cefuroxime was performed at 72 °C for 20 s, with fluorescence detection at (50 μg/mL) or ampicillin (50 μg/mL), cells were collected washed 72 °C after each cycle. After the final cycle, melting-point anal- and suspended in TRI Reagent (Molecular Research Center). yses of all samples were performed within the range of 62–95 °C RNA was extracted from samples and used to prepare probes for with continuous fluorescence detection. A standard curve was gene array in accord with the manufacturer’s instructions (Super- generated from one sample in each run. Expression levels of β2- Array Bioscience). Adequate labeling of the probes was tested microglobulin (B2M) were used for sample normalization before hybridization. Three healthy donors were tested in stim- (β-actin levels were affected by cefuroxime treatment). The primer ulation with cefuroxime. The membranes were analyzed online sequences were B2M sense TAGCTCTAGGAGGGCTG anti- with the Image Data Acquisition and Expression Analysis (Super- sense ACCACAACCATGCCTTA; ACVR2 sense ATCTCC- Array Bioscience). -
A Yeast Phenomic Model for the Influence of Warburg Metabolism on Genetic Buffering of Doxorubicin Sean M
Santos and Hartman Cancer & Metabolism (2019) 7:9 https://doi.org/10.1186/s40170-019-0201-3 RESEARCH Open Access A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin Sean M. Santos and John L. Hartman IV* Abstract Background: The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance. Methods: Cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy. Results: Yeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context. -
The Role of the NFAT Signalling Pathway in Diffuse Large B-Cell Lymphoma
The role of the NFAT signalling pathway in Diffuse Large B-cell Lymphoma Holly White Doctor of Philosophy Thesis September 2015 Supervisors: Dr Chris Bacon, Professor Neil Perkins & Dr Vikki Rand Northern Institute for Cancer Research Word count: 66,024 1 Abstract Diffuse Large B-Cell Lymphomas (DLBCL) are common, aggressive malignancies of mature B-lymphocytes that represent ~40% of lymphomas. Despite the widespread use of combined immunochemotherapy, approximately 50% of patients with DLBCL die from their disease. The two main DLBCL subgroups resemble activated B cells (ABC) or germinal centre B cells (GCB), where patients with ABC-DLBCL have significantly worse outcome. There is urgent need for novel therapeutic strategies in the treatment of DLBCL, which requires a better understanding of the molecular pathways upon which tumours depend. Accumulating evidence suggests that the signalling networks promoting and sustaining DLBCL derive from dysregulation of the normal pathways controlling B-lymphocyte activation and differentiation. There is increasing evidence indicating important roles for the NFAT family of transcription factors in DLBCL. Constitutively-active nuclear NFAT2 has been demonstrated in approximately 40% of primary DLBCL samples and NFAT has been shown to regulate a small number of genes associated with DLBCL growth/survival. This project investigated the role of NFAT in DLBCL. Nuclear localisation and activation of NFAT family members were characterised in a panel of DLBCL cell lines and chemical inhibition of calcineurin/NFAT, using Cyclosporin A (CsA), indicated dependency on the calcineurin/NFAT pathway for survival. Gene expression microarray analysis performed in DLBCL cell lines treated with CsA revealed potential NFAT target genes involved in the tumour microenvironment and anergy.