DOCSLIB.ORG

HIRA Orchestrates a Dynamic Chromatin Landscape in Senescence and Is Required for Suppression of Neoplasia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
HIRA Orchestrates a Dynamic Chromatin Landscape in Senescence and Is Required for Suppression of Neoplasia Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia Taranjit Singh Rai,1,2,3 John J. Cole,1,2,5 David M. Nelson,1,2,5 Dina Dikovskaya,1,2 William J. Faller,1 Maria Grazia Vizioli,1,2 Rachael N. Hewitt,1,2 Orchi Anannya,1 Tony McBryan,1,2 Indrani Manoharan,1,2 John van Tuyn,1,2 Nicholas Morrice,1 Nikolay A. Pchelintsev,1,2 Andre Ivanov,1,2,4 Claire Brock,1,2 Mark E. Drotar,1,2 Colin Nixon,1 William Clark,1 Owen J. Sansom,1 Kurt I. Anderson,1 Ayala King,1 Karen Blyth,1 and Peter D. Adams1,2 1Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; 2Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom; 3Institute of Biomedical and Environmental Health Research, University of West of Scotland, Paisley PA1 2BE, United Kingdom Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in non- proliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene- induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression. [Keywords: chromatin; senescence; HIRA; H4K16ac; dynamic; tumor suppression] Supplemental material is available for this article. Received June 15, 2014; revised version accepted November 4, 2014. Cellular senescence is a stable proliferation arrest asso- (Cosme-Blanco et al. 2007; Feldser and Greider 2007). The ciated with an altered proinflammatory secretory path- altered secretory program of senescent cells, comprised of way (Salama et al. 2014). In response to acquisition of an proinflammatory cytokines, chemokines, and matrix pro- activated oncogene, primary human cells enter this pro- teases (the senescence-associated secretory phenotype liferation-arrested senescent state (oncogene-induced se- [SASP]) (Krtolica et al. 2001; Acosta et al. 2008; Kuilman nescence [OIS]). By imposing proliferation arrest, OIS acts et al. 2008), can also contribute to tumor suppression as a tumor suppressor mechanism (Braig et al. 2005; Chen by promoting clearance of some senescent cells by et al. 2005; Collado et al. 2005; Michaloglou et al. 2005). the immune system (Xue et al. 2007; Kang et al. 2011; Even in the absence of an activated oncogene, replicative Lujambio et al. 2013). senescence (RS) places an upper limit on the proliferative Extensive chromatin changes are apparent in senescent capacity of normal cells, also blocking tumor formation cells, most obviously in the form of domains of compacted 4Present address: Barts, The London School of Medicine and Dentistry, Barts Cancer Institute, Queen Mary University of London, London EC1M Ó 2014 Rai et al. This article is distributed exclusively by Cold Spring 6BQ, United Kingdom Harbor Laboratory Press for the first six months after the full-issue 5These authors contributed equally to this work. publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding authors: [email protected], taranjitsingh.rai@uws. After six months, it is available under a Creative Commons License ac.uk (Attribution-NonCommercial 4.0 International), as described at http:// Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.247528.114. creativecommons.org/licenses/by-nc/4.0/. 2712 GENES & DEVELOPMENT 28:2712–2725 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/14; www.genesdev.org Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press HIRA mediates tumor suppression heterochromatin called senescence-associated hetero- is required for deposition of histone H3.3 at active and chromatin foci (SAHF) (Narita et al. 2003, 2006; Braig poised genes and enhancers (Goldberg et al. 2010; Ray- et al. 2005; Zhang et al. 2005; O’Sullivan et al. 2010; Gallet et al. 2011; Pchelintsev et al. 2013). Accordingly, Chandra et al. 2012; Cruickshanks et al. 2013; De Cecco HIRA is required for gene activation in some contexts et al. 2013; Sadaie et al. 2013; Shah et al. 2013). These and (Placek et al. 2009; Dutta et al. 2010; Yang et al. 2011) as other chromatin changes are thought to contribute to the well as recruitment and function of polycomb complexes onset and maintenance of viable senescence-associated at gene promoters and dynamic restoration of chromatin proliferation arrest (Braig et al. 2005; Narita et al. 2006; after DNA damage repair (Adam et al. 2013; Banaszynski Di Micco et al. 2011; Benhamed et al. 2012; Cruickshanks et al. 2013). On the other hand, the HIRA complex and its et al. 2013; Martin et al. 2013). Chromatin changes likely orthologs, together with histone H3.3, are also involved also contribute to activation of the SASP in senescent in chromatin silencing (Sherwood et al. 1993; van der cells (Shah et al. 2013). Subunits of the SWI/SNF ATP- Heijden et al. 2007). Importantly, several recent studies dependent chromatin remodeling complex are targets of have shown histone H3.3 to be a target of recurrent mutation and inactivation in cancer (Wilson and Roberts missense mutations in human cancer, and transcription- 2011), and SWI/SNF is thought to contribute to tumor coupled methylation of histone H3.3 is also thought to be suppression in part through induction of senescence tumor-suppressive (Schwartzentruber et al. 2012; Wu (Chai et al. 2005). In sum, several lines of evidence et al. 2012; Wen et al. 2014; Zhu et al. 2014). Appropri- indicate that chromatin of senescent cells contributes ately for a DNA replication-independent chaperone, to tumor suppression (Braig et al. 2005; Narita et al. HIRA is also involved in control of chromatin in non- 2006). However, the molecular basis of this is poorly proliferating senescent cells (Zhang et al. 2005; Ye et al. understood. 2007; Banumathy et al. 2009; Rai et al. 2011; Duarte et al. Specifically, SAHF have been suggested to contribute to 2014). However, HIRA’s function in senescent cells is stable repression of proliferation genes and/or suppres- poorly defined, and there is currently no direct evidence sion of DNA damage signaling in senescent cells (Narita for a role in tumor suppression. et al. 2003; Zhang et al. 2007; Di Micco et al. 2011). Either Here we set out to better understand dynamic chroma- way, the apparent heterochromatinization of senescent tin regulation in nonproliferating senescent cells and the cells intuitively suggests that their compacted, stable role of HIRA in this process. We reveal chromatin in chromatin contributes to a senescence-mediated barrier senescent cells to be a dynamic landscape linked to to tumor progression. In line with this view of relatively noncanonical regulation of histone mRNAs and excep- static chromatin in senescent cells, compared with pro- tional marking by H4K16ac. The histone chaperone liferating cells, senescent cells synthesize less total HIRA is required for regulation of this landscape and also histone H3 and H4 (O’Sullivan et al. 2010). In fact, in for suppression of oncogene-induced neoplasia in a mouse mammalian cells, the canonical DNA replication-depen- model. This study points to shared roles of HIRA, histone dent histones—H2A, H2B, H3 (H3.1 and H3.2), and H4— H3.3, and H4K16ac in both cellular senescence and tumor are each coded for by 10–15 genes located mostly in suppression. clusters on chromosomes 1 and 6, and the corresponding mRNAs are typically unstable in nonproliferating cells Results (Marzluff et al. 2008). This is again consistent with the view that chromatin in nonproliferating senescent cells The mRNAs encoding the canonical DNA replication- is a relatively fixed entity, intuitively suggestive of an dependent histones are generally regarded as unstable in immobile barrier to tumor progression. However, the nonproliferating cells (Marzluff et al. 2008). Moreover, extent of chromatin dynamics in senescent cells has not compared with proliferating cells, senescent cells synthe- been properly investigated. size less total histone H3 and H4 (O’Sullivan et al. 2010). Histone variant H3.3 contributes to nucleosome de- We were surprised, therefore, when gene expression stabilization (Jin and Felsenfeld 2007) and so is thought to microarray revealed that a subset of histone mRNAs facilitate nucleosome dynamics associated with tran- was apparently up-regulated in RS cells (senescence scription activation and ongoing transcription. Histone confirmed by standard markers of senescence) (Fig. 1A; H3.3 is enriched at nucleosomes at transcription start Supplemental Data Set 1; Supplemental Fig. 1A,B). Close sites (TSSs) of genes and at enhancers and gene bodies of examination showed that these are typically canonical actively transcribed genes (Ahmad and Henikoff 2002; Jin DNA replication-dependent histones from the HIST1 et al. 2009; Goldberg et al.
Load more

Recommended publications
  • Histone Isoform H2A1H Promotes Attainment of Distinct Physiological
    Bhattacharya et al. Epigenetics & Chromatin (2017) 10:48 DOI 10.1186/s13072-017-0155-z Epigenetics & Chromatin RESEARCH Open Access Histone isoform H2A1H promotes attainment of distinct physiological states by altering chromatin dynamics Saikat Bhattacharya1,4,6, Divya Reddy1,4, Vinod Jani5†, Nikhil Gadewal3†, Sanket Shah1,4, Raja Reddy2,4, Kakoli Bose2,4, Uddhavesh Sonavane5, Rajendra Joshi5 and Sanjay Gupta1,4* Abstract Background: The distinct functional efects of the replication-dependent histone H2A isoforms have been dem- onstrated; however, the mechanistic basis of the non-redundancy remains unclear. Here, we have investigated the specifc functional contribution of the histone H2A isoform H2A1H, which difers from another isoform H2A2A3 in the identity of only three amino acids. Results: H2A1H exhibits varied expression levels in diferent normal tissues and human cancer cell lines (H2A1C in humans). It also promotes cell proliferation in a context-dependent manner when exogenously overexpressed. To uncover the molecular basis of the non-redundancy, equilibrium unfolding of recombinant H2A1H-H2B dimer was performed. We found that the M51L alteration at the H2A–H2B dimer interface decreases the temperature of melting of H2A1H-H2B by ~ 3 °C as compared to the H2A2A3-H2B dimer. This diference in the dimer stability is also refected in the chromatin dynamics as H2A1H-containing nucleosomes are more stable owing to M51L and K99R substitu- tions. Molecular dynamic simulations suggest that these substitutions increase the number of hydrogen bonds and hydrophobic interactions of H2A1H, enabling it to form more stable nucleosomes. Conclusion: We show that the M51L and K99R substitutions, besides altering the stability of histone–histone and histone–DNA complexes, have the most prominent efect on cell proliferation, suggesting that the nucleosome sta- bility is intimately linked with the physiological efects observed.
    [Show full text]
  • 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 ....................................................................................................................
    [Show full text]
  • Analysis of Trans Esnps Infers Regulatory Network Architecture
    Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation.
    [Show full text]
  • Table S1. 49 Histone Variants Were Identified with High Sequence Coverage Through LC-MS/MS Analysis Electronic Supplementary
    Electronic Supplementary Material (ESI) for Analytical Methods. This journal is © The Royal Society of Chemistry 2020 Table S1. 49 histone variants were identified with high sequence coverage through LC-MS/MS analysis Sequence Uniprot IDs Protein Name Protein Description Coverage Ratio E2+/E2- RSD P07305 H10_HUMAN 67.5% Histone H1.0 OS=Homo sapiens GN=H1F0 PE=1 SV=3 4.85 23.3% Histone H1.1 OS=Homo sapiens GN=HIST1H1A PE=1 Q02539 H11_HUMAN 74.4% SV=3 0.35 92.6% Histone H1.2 OS=Homo sapiens GN=HIST1H1C PE=1 P16403 H12_HUMAN 67.1% SV=2 0.73 80.6% Histone H1.3 OS=Homo sapiens GN=HIST1H1D PE=1 P16402 H13_HUMAN 63.8% SV=2 0.75 77.7% Histone H1.4 OS=Homo sapiens GN=HIST1H1E PE=1 P10412 H14_HUMAN 69.0% SV=2 0.70 80.3% Histone H1.5 OS=Homo sapiens GN=HIST1H1B PE=1 P16401 H15_HUMAN 79.6% SV=3 0.29 98.3% Testis-specific H1 histone OS=Homo sapiens GN=H1FNT Q75WM6 H1FNT_HUMAN 7.8% \ \ PE=2 SV=3 Histone H1oo OS=Homo sapiens GN=H1FOO PE=2 Q8IZA3 H1FOO_HUMAN 5.2% \ \ SV=1 Histone H1t OS=Homo sapiens GN=HIST1H1T PE=2 P22492 H1T_HUMAN 31.4% SV=4 1.42 65.0% Q92522 H1X_HUMAN 82.6% Histone H1x OS=Homo sapiens GN=H1FX PE=1 SV=1 1.15 33.2% Histone H2A type 1 OS=Homo sapiens GN=HIST1H2AG P0C0S8 H2A1_HUMAN 99.2% PE=1 SV=2 0.57 26.8% Q96QV6 H2A1A_HUMAN 58.0% Histone H2A type 1-A OS=Homo sapiens 0.90 11.2% GN=HIST1H2AA PE=1 SV=3 Histone H2A type 1-B/E OS=Homo sapiens P04908 H2A1B_HUMAN 99.2% GN=HIST1H2AB PE=1 SV=2 0.92 30.2% Histone H2A type 1-C OS=Homo sapiens Q93077 H2A1C_HUMAN 100.0% GN=HIST1H2AC PE=1 SV=3 0.76 27.6% Histone H2A type 1-D OS=Homo sapiens P20671
    [Show full text]
  • The Landscape of Somatic Mutations in Epigenetic Regulators Across 1,000 Paediatric Cancer Genomes
    ARTICLE Received 24 Sep 2013 | Accepted 12 Mar 2014 | Published 8 Apr 2014 DOI: 10.1038/ncomms4630 The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes Robert Huether1,*, Li Dong2,*, Xiang Chen1, Gang Wu1, Matthew Parker1, Lei Wei1, Jing Ma2, Michael N. Edmonson1, Erin K. Hedlund1, Michael C. Rusch1, Sheila A. Shurtleff2, Heather L. Mulder3, Kristy Boggs3, Bhavin Vadordaria3, Jinjun Cheng2, Donald Yergeau3, Guangchun Song2, Jared Becksfort1, Gordon Lemmon1, Catherine Weber2, Zhongling Cai2, Jinjun Dang2, Michael Walsh4, Amanda L. Gedman2, Zachary Faber2, John Easton3, Tanja Gruber2,4, Richard W. Kriwacki5, Janet F. Partridge6, Li Ding7,8,9, Richard K. Wilson7,8,9, Elaine R. Mardis7,8,9, Charles G. Mullighan2, Richard J. Gilbertson10, Suzanne J. Baker10, Gerard Zambetti6, David W. Ellison2, Jinghui Zhang1 & James R. Downing2 Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity.
    [Show full text]
  • Differences for Ectopic Versus Eutopic Cells
    556 RBMO VOLUME 39 ISSUE 4 2019 ARTICLE Chemosensitivity and chemoresistance in endometriosis – differences for ectopic versus eutopic cells BIOGRAPHY Andres Salumets is Professor of Reproductive Medicine at the University of Tartu, and Scientific Head at the Competence Centre on Health Technologies, Tartu, Estonia. He has been involved in assisted reproduction for 20 years, first as an embryologist and later as a researcher. His major interests are endometriosis, endometrial biology and implantation. Darja Lavogina1,2,*, Külli Samuel1, Arina Lavrits1,3, Alvin Meltsov1, Deniss Sõritsa1,4,5, Ülle Kadastik6, Maire Peters1,4, Ago Rinken2, Andres Salumets1,4,7, 8 KEY MESSAGE Akt/PKB inhibitor GSK690693, CK2 inhibitor ARC-775, MAPK pathway inhibitor sorafenib, proteasome inhibitor bortezomib, and microtubule-depolymerizing toxin MMAE showed higher cytotoxicity in eutopic cells. In contrast, 10 µmol/l of the anthracycline toxin doxorubicin caused cellular death in ectopic cells more effectively than in eutopic cells, underlining the potential of doxorubicin in endometriosis research. ABSTRACT Research question: Endometriosis is a common gynaecological disease defined by the presence of endometrium-like tissue outside the uterus. This complex disease, often accompanied by severe pain and infertility, causes a significant medical and socioeconomic burden; hence, novel strategies are being sought for the treatment of endometriosis. Here, we set out to explore the cytotoxic effects of a panel of compounds to find toxins with different efficiency in eutopic versus ectopic cells, thus highlighting alterations in the corresponding molecular pathways. Design: The effect on cellular viability of 14 compounds was established in a cohort of paired eutopic and ectopic endometrial stromal cell samples from 11 patients.
    [Show full text]
  • DNA Methylation Changes in Down Syndrome Derived Neural Ipscs Uncover Co-Dysregulation of ZNF and HOX3 Families of Transcription
    Laan et al. Clinical Epigenetics (2020) 12:9 https://doi.org/10.1186/s13148-019-0803-1 RESEARCH Open Access DNA methylation changes in Down syndrome derived neural iPSCs uncover co- dysregulation of ZNF and HOX3 families of transcription factors Loora Laan1†, Joakim Klar1†, Maria Sobol1, Jan Hoeber1, Mansoureh Shahsavani2, Malin Kele2, Ambrin Fatima1, Muhammad Zakaria1, Göran Annerén1, Anna Falk2, Jens Schuster1 and Niklas Dahl1* Abstract Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages. Results: Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling. Conclusions: The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.
    [Show full text]
  • Functional Annotations of Single-Nucleotide Polymorphism
    CLINICAL RESEARCH e-ISSN 1643-3750 © Med Sci Monit, 2020; 26: e922710 DOI: 10.12659/MSM.922710 Received: 2020.01.08 Accepted: 2020.02.20 Functional Annotations of Single-Nucleotide Available online: 2020.03.30 Published: 2020.05.25 Polymorphism (SNP)-Based and Gene-Based Genome-Wide Association Studies Show Genes Affecting Keratitis Susceptibility Authors’ Contribution: BCDEF 1 Yue Xu* 1 Department of Ophthalmology, First Affiliated Hospital of Soochow University, Study Design A BCDEF 2 Xiao-Lin Yang* Suzhou, Jiangsu, P.R. China Data Collection B 2 Center for Genetic Epidemiology and Genomics, School of Public Health, Medical Statistical Analysis C BCD 1 Xiao-Long Yang College of Soochow University, Suzhou, Jiangsu, P.R. China Data Interpretation D BC 1 Ya-Ru Ren Manuscript Preparation E BC 1 Xin-Yu Zhuang Literature Search F Funds Collection G ADE 2 Lei Zhang ADE 1 Xiao-Feng Zhang * Yue Xu and Xiao-Lin Yang contributed equally Corresponding Authors: Xiao-Feng Zhang, e-mail: [email protected], Lei Zhang, e-mail: [email protected] Source of support: Departmental sources Background: Keratitis is a complex condition in humans and is the second most common cause of legal blindness worldwide. Material/Methods: To reveal the genomic loci underlying keratitis, we performed functional annotations of SNP-based and gene- based genome-wide association studies of keratitis in the UK Biobank (UKB) cohort with 337 199 subjects of European ancestry. Results: The publicly available SNP-based association results showed a total of 34 SNPs, from 14 distinct loci, associated with keratitis in the UKB. Gene-based association analysis identified 2 significant genes:IQCF3 (p=2.0×10–6) and SOD3 (p=2.0×10–6).
    [Show full text]
  • Hira Peracha a Thesis
    DIAGNOSIS METHOD FOR MUCOPOLYSACCHARIDOSES by Hira Peracha A thesis submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Bachelor of Arts in Biological Sciences with Distinction Spring 2018 © 2018 Hira Peracha All Rights Reserved i DIAGNOSIS METHOD FOR MUCOPOLYSACCHARIDOSES by Hira Peracha Approved: __________________________________________________________ Shunji Tomatsu, MD, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Deni Galileo, Ph.D. Professor in charge of thesis on behalf of the Advisory Committee Approved: __________________________________________________________ Jessica Tanis, Ph.D. Committee member from the Department of Department Name Approved: __________________________________________________________ Barbara Settles, Ph.D. Committee member from the Board of Senior Thesis Readers Approved: __________________________________________________________ Michael Chajes, Ph.D. Chair of the University Committee on Student and Faculty Honors ii “Education is the key to unlocking the world, a passport to freedom.” -Oprah Winfrey iii ACKNOWLEDGMENTS I dedicate my thesis to my late grandfather, who taught me the value of life, hard work and sacrifice- especially in sickness and in health. I would like to express my deepest acknowledgements to my family. I could not have achieved all of my dreams and goals in life without my parents; my mom and my dad, whose sacrifices, love and support have been endless and infinite. Thank you for raising me to believe that anything was possible, and for spending your entire lives to better mine. To my younger siblings, Saarah, Hafsah and Arif, who have been the light in the dark times in my life and have always brought joy and happiness in my life.
    [Show full text]
  • M2139: Molecular Analysis for Gliomas
    Molecular Analysis for Gliomas Policy Number: AHS – M2139 – Molecular Analysis Prior Policy Name and Number, as applicable: for Gliomas • AHS – M2139 – Analysis of MGMT Promoter Methylation for Malignant Gliomas Initial Presentation Date: 06/16/2021 Revision Date: N/A I. Policy Description Glioma refers to tumors resulting from metaplastic transformation of glial tissue of the nervous system. Tumors have historically been classified by the retained histologic features of the three types of glial cells: astrocytes, oligodendrocytes, and ependymal cells. Tumors of each type can vary widely in aggressiveness, response to treatment, and prognosis (Louis, Schiff, & Batchelor, 2020). Molecular genetic features were added to histopathologic appearance in the current WHO classification to yield more biologically homogeneous and narrowly defined diagnostic entities for greater diagnostic accuracy, improved patient management, more accurate determinations of prognosis, and better treatment response (Louis et al., 2016). II. Related Policies Policy Number Policy Title AHS-M2109 Molecular Panel Testing of Cancers for Diagnosis, Prognosis, and Identification of Targeted Therapy III. Indications and/or Limitations of Coverage Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request 1. MGMT promoter methylation testing IS MEDICALLY NECESSARY for prognosis of malignant gliomas. 2. IDH1 and IDH2 testing IS MEDICALLY NECESSARY for prognosis of malignant gliomas. M2139 Molecular Analysis for Gliomas Page 1 of 15 3. Testing for the co-deletion of 1p and 19q by either fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for the characterization of gliomas and/or to guide treatment decisions IS MEDICALLY NECESSARY. 4. ATRX mutation testing via EITHER immunohistochemistry OR gene sequencing IS MEDICALLY NECESSARY for the prognosis of malignant gliomas.
    [Show full text]
  • Anti-Histone H2B Antibody (ARG41373)
    Product datasheet [email protected] ARG41373 Package: 100 μl anti-Histone H2B antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes Histone H2B Tested Reactivity Hu, Ms, Rat Tested Application FACS, ICC/IF, IHC-P, IP, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name Histone H2B Antigen Species Human Immunogen Synthetic peptide derived from Human Histone H2B. Conjugation Un-conjugated Alternate Names Histone H2B type 1-K; H2BFAiii; H2BFT; H2B/S; H2B K; H2BK; HIRA-interacting protein 1 Application Instructions Application table Application Dilution FACS 1:50 ICC/IF 1:50 - 1:200 IHC-P 1:50 - 1:200 IP 1:30 WB 1:5000 - 1:20000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Calculated Mw 14 kDa Observed Size ~ 14 kDa Properties Form Liquid Purification Affinity purified. Buffer PBS (pH 7.4), 150 mM NaCl, 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot www.arigobio.com 1/2 and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Gene Symbol HIST1H2BK Gene Full Name histone cluster 1, H2bk Background Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes.
    [Show full text]
  • Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
    Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology.
    [Show full text]