Tyr1 Phosphorylation Promotes Phosphorylation of Ser2 on the C-Terminal Domain
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Human Prion-Like Proteins and Their Relevance in Disease
ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Universitat Autònoma de Barcelona Departament de Bioquímica i Biologia Molecular Institut de Biotecnologia i Biomedicina HUMAN PRION-LIKE PROTEINS AND THEIR RELEVANCE IN DISEASE Doctoral thesis presented by Cristina Batlle Carreras for the degree of PhD in Biochemistry, Molecular Biology and Biomedicine from the Universitat Autònoma de Barcelona. The work described herein has been performed in the Department of Biochemistry and Molecular Biology and in the Institute of Biotechnology and Biomedicine, supervised by Prof. Salvador Ventura i Zamora. Cristina Batlle Carreras Prof. Salvador Ventura i Zamora Bellaterra, 2020 Protein Folding and Conformational Diseases Lab. This work was financed with the fellowship “Formación de Profesorado Universitario” by “Ministerio de Ciencia, Innovación y Universidades”. This work is licensed under a Creative Commons Attributions-NonCommercial-ShareAlike 4.0 (CC BY-NC- SA 4.0) International License. The extent of this license does not apply to the copyrighted publications and images reproduced with permission. (CC BY-NC-SA 4.0) Batlle, Cristina: Human prion-like proteins and their relevance in disease. Doctoral Thesis, Universitat Autònoma de Barcelona (2020) English summary ENGLISH SUMMARY Prion-like proteins have attracted significant attention in the last years. -
A Network Propagation Approach to Prioritize Long Tail Genes in Cancer
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.05.429983; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A Network Propagation Approach to Prioritize Long Tail Genes in Cancer Hussein Mohsen1,*, Vignesh Gunasekharan2, Tao Qing2, Sahand Negahban3, Zoltan Szallasi4, Lajos Pusztai2,*, Mark B. Gerstein1,5,6,3,* 1 Computational Biology & Bioinformatics Program, Yale University, New Haven, CT 06511, USA 2 Breast Medical Oncology, Yale School of Medicine, New Haven, CT 06511, USA 3 Department of Statistics & Data Science, Yale University, New Haven, CT 06511, USA 4 Children’s Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA 5 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA 6 Department of Computer Science, Yale University, New Haven, CT 06511, USA * Corresponding author Abstract Introduction. The diversity of genomic alterations in cancer pose challenges to fully understanding the etiologies of the disease. Recent interest in infrequent mutations, in genes that reside in the “long tail” of the mutational distribution, uncovered new genes with significant implication in cancer development. The study of these genes often requires integrative approaches with multiple types of biological data. Network propagation methods have demonstrated high efficacy in uncovering genomic patterns underlying cancer using biological interaction networks. Yet, the majority of these analyses have focused their assessment on detecting known cancer genes or identifying altered subnetworks. -
Proteogenomic Analysis of Inhibitor of Differentiation 4 (ID4) in Basal-Like Breast Cancer Laura A
Baker et al. Breast Cancer Research (2020) 22:63 https://doi.org/10.1186/s13058-020-01306-6 RESEARCH ARTICLE Open Access Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer Laura A. Baker1,2, Holly Holliday1,2†, Daniel Roden1,2†, Christoph Krisp3,4†, Sunny Z. Wu1,2, Simon Junankar1,2, Aurelien A. Serandour5, Hisham Mohammed5, Radhika Nair6, Geetha Sankaranarayanan5, Andrew M. K. Law1,2, Andrea McFarland1, Peter T. Simpson7, Sunil Lakhani7,8, Eoin Dodson1,2, Christina Selinger9, Lyndal Anderson9,10, Goli Samimi11, Neville F. Hacker12, Elgene Lim1,2, Christopher J. Ormandy1,2, Matthew J. Naylor13, Kaylene Simpson14,15, Iva Nikolic14, Sandra O’Toole1,2,9,10, Warren Kaplan1, Mark J. Cowley1,2, Jason S. Carroll5, Mark Molloy3 and Alexander Swarbrick1,2* Abstract Background: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. Methods: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
POLR2C Mutations Are Associated with Primary Ovarian Insufficiency in Women
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author J Endocr Manuscript Author Soc. Author manuscript; Manuscript Author available in PMC 2017 October 20. Published in final edited form as: J Endocr Soc. 2017 March 1; 1(3): 162–173. doi:10.1210/js.2016-1014. POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women Mika Moriwaki1, Barry Moore2, Timothy Mosbruger3, Deborah W. Neklason4, Mark Yandell2, Lynn B. Jorde2, and Corrine K. Welt1 1Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah 84112 2UStar Center for Genetic Discovery, Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112 3Bioinformatics, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112 4Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112 Abstract Context—Primary ovarian insufficiency (POI) results from a premature loss of oocytes, causing infertility and early menopause. The etiology of POI remains unknown in a majority of cases. Objective—To identify candidate genes in families affected by POI. Design—This was a family-based genetic study. Setting—The study was performed at two academic institutions. Patients and Other Participants—A family with four generations of women affected by POI (n = 5). Four of these women, three with an associated autoimmune diagnosis, were studied. The controls (n = 387) were recruited for health in old age. Intervention—Whole-genome sequencing was performed. Main Outcome Measure—Candidate genes were identified by comparing gene mutations in three family members and 387 control subjects analyzed simultaneously using the pedigree Variant Annotation, Analysis and Search Tool. -
Supplemental Digital Content (Sdc) Sdc, Materials
SUPPLEMENTAL DIGITAL CONTENT (SDC) SDC, MATERIALS AND METHODS Animals This study used 9-12 week old male C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME). This study conformed to the National Institutes of Health guidelines and was conducted under animal protocols approved by the University of Virginia’s Institutional Animal Care and Use Committee. Murine DCD Lung Procedure Mice were anesthetized by isoflurane inhalation and euthanized by cervical dislocation followed by a 60-minute period of “no-touch” warm ischemia. Mice then underwent extended median sternotomy and midline cervical exposure followed by intubation for the initiation of mechanical ventilation at 120 strokes/minute with room air. The left atrium was vented via an atriotomy followed by infusion of the lungs with 3 mL 4°C Perfadex® solution (Vitrolife Inc., Denver, CO) supplemented with THAM Solution (Vitrolife, Kungsbacka, Sweden), estimating weight-based volume recommendations for pulmonary artery perfusion (140mL/kg) (1). The chest was then packed with ice and the trachea occluded by silk-suture tie at tidal volume (7µL/g body weight) prior to cold static preservation (CSP) for 60 minutes at 4°C. Mice were then randomized into three experimental groups: 1) CSP alone with no EVLP, 2) EVLP with Steen solution and 3) EVLP with Steen solution supplemented with the highly selective A2AR agonist, ATL1223 (30nM, Lewis and Clark Pharmaceuticals, Charlottesville, VA). Mice treated with ATL1223 during EVLP also received ATL1223 treatment (30nM) during the Perfadex flush prior to CSP whereas the EVLP group received vehicle (DMSO) during the flush. CSP lungs, which did not undergo EVLP, underwent immediate functional assessment after re-intubation as described below. -
Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: a Bioinformatics Approach
International Journal of Molecular Sciences Article Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach Theodora-Christina Kyriakou 1, Panagiotis Papageorgis 1,2 and Maria-Ioanna Christodoulou 3,* 1 Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus; [email protected] (T.-C.K.); [email protected] (P.P.) 2 European University Cyprus Research Center, Nicosia 2404, Cyprus 3 Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus * Correspondence: [email protected] Abstract: Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise Citation: Kyriakou, T.-C.; common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, Papageorgis, P.; Christodoulou, M.-I. may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and Common Genetic Aberrations RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. -
WO 2014/134728 Al 12 September 2014 (12.09.2014) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/134728 Al 12 September 2014 (12.09.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) G06F 19/20 (201 1.01) kind of national protection available): AE, AG, AL, AM, C40B 30/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/CA20 14/050 174 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 6 March 2014 (06.03.2014) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/774,271 7 March 2013 (07.03.2013) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicants: UNIVERSITE DE MONTREAL [CA/CA]; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 2900 Edouard-Montpetit, Montreal, Quebec H3T 1J4 UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (CA). -
Parent-Of-Origin Effects on Quantitative Phenotypes in a Large Hutterite Pedigree
ARTICLE https://doi.org/10.1038/s42003-018-0267-4 OPEN Parent-of-origin effects on quantitative phenotypes in a large Hutterite pedigree Sahar V. Mozaffari 1,2, Jeanne M. DeCara3, Sanjiv J. Shah4, Carlo Sidore5, Edoardo Fiorillo5, Francesco Cucca5,6, Roberto M. Lang3, Dan L. Nicolae1,2,3,7 & Carole Ober1,2 1234567890():,; The impact of the parental origin of associated alleles in GWAS has been largely ignored. Yet sequence variants could affect traits differently depending on whether they are inherited from the mother or the father, as in imprinted regions, where identical inherited DNA sequences can have different effects based on the parental origin. To explore parent-of-origin effects (POEs), we studied 21 quantitative phenotypes in a large Hutterite pedigree to identify variants with single parent (maternal-only or paternal-only) effects, and then variants with opposite parental effects. Here we show that POEs, which can be opposite in direction, are relatively common in humans, have potentially important clinical effects, and will be missed in traditional GWAS. We identified POEs with 11 phenotypes, most of which are risk factors for cardiovascular disease. Many of the loci identified are characteristic of imprinted regions and are associated with the expression of nearby genes. 1 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. 2 Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL 60637, USA. 3 Department of Medicine, University of Chicago, Chicago, IL 60637, USA. 4 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 5 Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato 09042, Italy. -
Genome-Wide Mapping and Analysis of Active Promoters in Mouse Embryonic Stem Cells and Adult Organs
Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs Leah O. Barrera,1,2,7 Zirong Li,1,7 Andrew D. Smith,3 Karen C. Arden,1,4 Webster K. Cavenee,1,4 Michael Q. Zhang,3 Roland D. Green,5,8 and Bing Ren1,6,8 1Ludwig Institute for Cancer Research, UCSD School of Medicine, La Jolla, California 92093-0653, USA; 2UCSD Bioinformatics Graduate Program, UCSD, La Jolla, California 92093-0653, USA; 3Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; 4Department of Medicine, UCSD School of Medicine, La Jolla, California 92093-0660, USA; 5NimbleGen Systems Inc., Madison, Wisconsin 53711, USA; 6Department of Cellular and Molecular Medicine, UCSD School of Medicine, La Jolla, California 92093-0653, USA By integrating genome-wide maps of RNA polymerase II (Polr2a) binding with gene expression data and H3ac and H3K4me3 profiles, we characterized promoters with enriched activity in mouse embryonic stem cells (mES) as well as adult brain, heart, kidney, and liver. We identified ∼24,000 promoters across these samples, including 16,976 annotated mRNA 5Ј ends and 5153 additional sites validating cap-analysis of gene expression (CAGE) 5Ј end data. We showed that promoters with CpG islands are typically non-tissue specific, with the majority associated with Polr2a and the active chromatin modifications in nearly all the tissues examined. By contrast, the promoters without CpG islands are generally associated with Polr2a and the active chromatin marks in a tissue-dependent way. -
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Analytical Methods Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/methods Page 1 of 6 Analytical Methods 1 2 Journal Name RSCPublishing 3 4 5 ARTICLE 6 7 8 9 Multiplexed Single-Cell In Situ RNA Analysis by 10 Reiterative Hybridization 11 Cite this: DOI: 10.1039/x0xx00000x 12 Lu Xiao, Jia Guo* 13 14 Most current approaches for quantification of RNA species in their natural spatial contexts in 15 single cells are limited by a small number of parallel analyses. Here we report a strategy to Received 00th January 2012, 16 Accepted 00th January 2012 dramatically increase the multiplexing capacity for RNA analysis in single cells in situ. -
Heterozygous Deletion of Chromosome 17P Renders Prostate Cancer Vulnerable to the Inhibition of RNA Polymerase II IMPROVING HEALTH THROUGH RESEARCH
Heterozygous Deletion of Chromosome 17p Renders Prostate Cancer Vulnerable to the Inhibition of RNA Polymerase II IMPROVING HEALTH THROUGH RESEARCH Yujing Li1, Xiongbin Lu1,2 indianactsi.org 1 Indiana University School of Medicine, Indianapolis Indiana; 2 Corresponding authors: XL ([email protected]) ABSTRACT RESULT 3 RESULT 6 Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discover that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2- mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppresses the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug loss conjugate (ADC). Given the limited therapeutic options for RBX1 depletion sensitized 17p prostate cancer cells to POLR2A inhibition. (a) RBX1 promotes RNA transcription. Global RNA synthesis was CRPC, our findings identify RBX1 as a potentially therapeutic CRISPR/Cas9-based screen identifies RBX1 as an essential gene evaluated by measurement of 5-EU incorporation and the intensity was loss target for treating human CRPC harboring heterozygous deletion selectively for the 17p prostate cancer cells. (a) Schematic illustration of quantified with the CellProfiler Software. (b) Effect of RBX1 knockdown on the of 17p.