DOCSLIB.ORG

Molecular Genetic Analysis of FAM58A and Expansion of the Mutation Spectrum in STAR Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Molecular Genetic Analysis of FAM58A and Expansion of the Mutation Spectrum in STAR Syndrome Inaugural-Dissertation zur Erlangung der Doktorwürde der Fakultät für Biologie der Albert-Ludwigs-Universität Freiburg im Breisgau vorgelegt von Alexander William Craig geboren in Bellefonte, Pa., USA Februar 2015 Angefertigt am Institut für Humangenetik der Universität Freiburg Dekan der Fakultät für Biologie: Prof. Dr. Wolfgang Driever Promotionsvorsitzender: Prof. Dr. Stefan Rotter Betreuer der Arbeit: Prof. Dr. Gerd Scherer Referent: Prof. Dr. Gerd Scherer Korreferent: Prof. Dr. Bernhard Zabel Drittprüfer: Prof. Dr. Wolfgang Driever Datum der mündlichen Prüfung: 13. Juli 2015 To Evelyne, Tove, and Elin IF I HAVE BEEN ABLE TO SEE FURTHER, IT IS BECAUSE I HAVE STOOD ON THE SHOULDERS OF GIANTS. ISAAC NEWTON SCIENCE ADVANCES ONLY BY MAKING ALL POSSIBLE MISTAKES; THE MAIN THING IS TO MAKE THE MISTAKES AS FAST AS POSSIBLE - AND RECOGNIZE THEM. JOHN ARCHIBALD WHEELER IT IS GOOD TO HAVE AN END TO JOURNEY TOWARD; BUT IT IS THE JOURNEY THAT MATTERS, IN THE END. ERNEST HEMINGWAY i Erklärung Die experimentellen Arbeiten für diese Dissertation wurden von Mai 2007 bis März 2010 im Institut für Humangenetik der Albert-Ludwigs-Universität Freiburg unter Anleitung von Prof. Dr. Gerd Scherer durchgeführt. 1. Ich erkläre hiermit, dass ich die vorliegende Arbeit ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe. Die aus anderen Quellen direkt oder indirekt übernommenen Daten und Konzepte sind unter Angabe der Quellen gekennzeichnet. Insbesondere habe ich hierfür nicht die entgeltliche Hilfe von Vermittlungs- beziehungsweise Beratungsdiensten (Promotionsberater oder anderer Personen) in Anspruch genommen. Niemand hat von mir unmittelbar oder mittelbar geldwerte Leistungen für Arbeiten erhalten, die im Zusammenhang mit dem Inhalt der vorgelegten Dissertation stehen. 2. Die Arbeit wurde bisher weder im In- noch im Ausland in gleicher oder ähnlicher Form einer anderen Prüfungsbehörde vorgelegt. 3. Die Bestimmungen der Promotionsordnung der Fakultät für Biologie sind mir bekannt, insbesondere weiß ich, dass ich vor Vollzug der Promotion zur Führung des Doktortitels nicht berechtigt bin. Statement of Veracity 1. I hereby certify that I have authored this thesis using no other means and references than those presented and/or cited in this work and without any improper help from third parties. This thesis is exclusively the product of my own investigations unless indicated otherwise through appropriate references or acknowledgment. Data and concepts derived directly or indirectly from other research are appropriately indicated citing the relevant sources. I have not resorted to the paid services of any agencies or advisors (companies and/or individuals, e.g. ghostwriters). No one received direct or indirect monetary benefit and/or financial reimbursement for services related to the contents of this academic dissertation. 2. This thesis has not been submitted in identical or similar form to any examination board/thesis committee in Germany or any other country. 3. I am aware of the stipulations laid down in the regulations for theses and dissertations by the Department of Biology. Specifically, I know that I am not entitled to using the doctoral title before completion of the promotion process. Freiburg, 5. Februar 2015 Freiburg, February 5, 2015 Alexander Craig ii Acknowledgments I am grateful for the environment and the people I encountered at the Institute of Human Genetics in Freiburg and thank all of my co-workers and colleagues for their technical assistance, scientific feed-back and a fun-time in and out of the lab. I thank Professor Jürgen Kohlhase for giving me the opportunity to work on this interesting topic and for his scientific input. I am especially indebted to Professor Gerd Scherer who hosted me in his lab, supported me in any way he could, made many valuable suggestions, who motivated me in times of doubt and always had an open ear and helpful advice. I am also much obliged to all the researchers in this field who shared their resources, information and thoughts and stimulated my own research. Dr. Sachin Deshmukh from the Center of Chronic Immunodeficiency at the University of Freiburg Medical Center was especially generous with antibodies and advice and my thanks go out to him. To my parents I owe my curiosity about the world, my love for science and the arts, and for making me see what matters in life. Last and most of all, I thank my partner Evelyne for all her support, for bearing with me during the work on this thesis, and for her constant gentle prodding. iii Results from this thesis have been published as articles in peer-reviewed journals and as conference abstracts: Unger S, Böhm D, Kaiser FJ, Kaulfuß S, Borozdin W, Buiting K, Burfeind P, Böhm J, Barrionuevo F, Craig A, Borowski K, Keppler-Noreuil K, Schmitt-Mechelke T, Steiner B, Bartholdi D, Lemke J, Mortier G, Sandford RN, Zabel B, Superti-Furga A, Kohlhase J (2008). Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nature Genetics 40: 287-289. A copy of this journal article has been appended to this thesis. Craig A, Zoll B, Rakenius A, Zappel H, Leube B, Bartz U, Heimdal K, Gener B, Borozdin W, Buiting K, Cobben JM, Kohlhase J (2010). Expansion of the STAR syndrome phenotype and evidence for genetic heterogeneity. Medizinische Genetik 22:107 Conference Abstract. Rakenius A, Zappel H, Borozdin W, Craig A, Gärtner J, Kohlhase J (2010). STAR syndrome and nephroblastoma – FAM58A linking organogenesis and tumorigenesis? European Journal of Pediatrics 169: 389. Conference Abstract. Contributions to other articles: Böhm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U (2008). Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Medical Genetics 9:88. doi: 10.1186/1471-2350-9-88. Note added in proof / errata: Compared to the version of February 2015, minor orthographical, punctuation, grammatical and stylistic errors and/or inconsistencies were corrected in preparing this document. A representational error in fig. 32 was corrected. The icons for "cell cycle regulators: cell cyle- dependent element" and "core promoter element, TATA-less promoters" were swapped. In figure 48, the sequence was amended to match the statements in the figure legend. iv Table of Contents Erklärung .......................................................................................................................................... i Acknowledgments .......................................................................................................................... ii TABLE OF CONTENTS ...........................................................................................IV ABSTRACT .............................................................................................................VII ZUSAMMENFASSUNG .........................................................................................VIII Abbreviations and Symbols ........................................................................................................... x Acronyms for proteins, cells, symptoms, and syndromes .............................................................................. x General abbreviations..................................................................................................................................... x 1. INTRODUCTION ................................................................................................... 1 1.1 STAR syndrome: clinical picture ............................................................................................. 1 1.2 Anorectal and urogenital malformations ................................................................................ 2 1.2.1 Epidemiological aspects ....................................................................................................................... 2 1.2.2 Manifestations of anorectal malformations: imperforate anus, fistulas, etc. ........................................ 3 1.2.3 Developmental origins of the anorectal and urogenital region ............................................................. 5 1.2.4 The origin of caudal defects ................................................................................................................. 8 1.2.5 Non-urological co-morbidities of anorectal malformations: the caudal phenotype ............................... 8 1.3 Genetic aspects of ARMs and/or UGMs ................................................................................. 8 1.3.1 Syndromic and non-syndromic manifestation of ARMs and UGMs ..................................................... 8 1.3.1 Animal models of ARMs and relevant Signaling Pathways .................................................................. 9 1.4 STAR Syndrome and FAM58A ............................................................................................... 11 1.4.1 FAM58A: gene, transcripts, protein .................................................................................................... 12 1.4.2 FAM58A: genomic context ................................................................................................................. 14 1.5 The cellular function of FAM58A ..........................................................................................
Recommended publications
  • Critical Climate Change

    Critical Climate Change

    Telemorphosis Critical Climate Change Series Editors: Tom Cohen and Claire Colebrook The era of climate change involves the mutation of sys- tems beyond 20th century anthropomorphic models and has stood, until recently, outside representation or address. Understood in a broad and critical sense, climate change concerns material agencies that impact on biomass and energy, erased borders and microbial invention, geological and nanographic time, and extinction events. The possibil- ity of extinction has always been a latent figure in textual production and archives; but the current sense of deple- tion, decay, mutation and exhaustion calls for new modes of address, new styles of publishing and authoring, and new formats and speeds of distribution. As the pressures and re- alignments of this re-arrangement occur, so must the critical languages and conceptual templates, political premises and definitions of ‘life.’ There is a particular need to publish in timely fashion experimental monographs that redefine the boundaries of disciplinary fields, rhetorical invasions, the in- terface of conceptual and scientific languages, and geomor- phic and geopolitical interventions. Critical Climate Change is oriented, in this general manner, toward the epistemo- political mutations that correspond to the temporalities of terrestrial mutation. Telemorphosis Theory in the Era of Climate Change Volume 1 Edited by Tom Cohen OPEN HUMANITIES PRESS An imprint of MPublishing – University of Michigan Library, Ann Arbor 2012 First edition published by Open Humanities Press 2012 Freely available online at http://hdl.handle.net/2027/spo.10539563.0001.001 Copyright © 2012 Ton Cohen and the respective authors This is an open access book, licensed under Creative Commons By Attribution Share Alike license.
  • Trex2 Enables Spontaneous Sister Chromatid Exchanges Without Facilitating DNA Double-Strand Break Repair

    Trex2 Enables Spontaneous Sister Chromatid Exchanges Without Facilitating DNA Double-Strand Break Repair

    INVESTIGATION Trex2 Enables Spontaneous Sister Chromatid Exchanges Without Facilitating DNA Double-Strand Break Repair Lavinia C. Dumitrache,*,1,2 Lingchuan Hu,*,1 Mi Young Son,* Han Li,*,3 Austin Wesevich,* Ralph Scully,† Jeremy Stark,‡ and Paul Hasty*,4 *Department of Molecular Medicine/Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245-3207, yDepartment of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center Division of Hematology– Oncology/Cancer Biology Program, Boston, Massachusetts 02115, and ‡Department of Cancer Biology, Division of Radiation Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 ABSTRACT Trex2 is a 39 / 59 exonuclease that removes 39-mismatched sequences in a biochemical assay; however, its biological function remains unclear. To address biology we previously generated trex2null mouse embryonic stem (ES) cells and expressed in these cells wild-type human TREX2 cDNA (Trex2hTX2) or cDNA with a single-amino-acid change in the catalytic domain (Trex2H188A) or in the DNA-binding domain (Trex2R167A). We found the trex2null and Trex2H188A cells exhibited spontaneous broken chromosomes and trex2null cells exhibited spontaneous chromosomal rearrangements. We also found ectopically expressed human TREX2 was active at the 39 ends of I-SceI–induced chromosomal double-strand breaks (DSBs). Therefore, we hypothesized Trex2 participates in DNA DSB repair by modifying 39 ends. This may be especially important for ends with damaged nucleotides. Here we present data that are unexpected and prompt a new model. We found Trex2-altered cells (null, H188A, and R167A) were not hypersensitive to campto- thecin, a type-1 topoisomerase inhibitor that induces DSBs at replication forks.
  • Linked Mental Retardation Detected by Array CGH

    Linked Mental Retardation Detected by Array CGH

    JMG Online First, published on September 16, 2005 as 10.1136/jmg.2005.036178 J Med Genet: first published as 10.1136/jmg.2005.036178 on 16 September 2005. Downloaded from Chromosomal copy number changes in patients with non-syndromic X- linked mental retardation detected by array CGH D Lugtenberg1, A P M de Brouwer1, T Kleefstra1, A R Oudakker1, S G M Frints2, C T R M Schrander- Stumpel2, J P Fryns3, L R Jensen4, J Chelly5, C Moraine6, G Turner7, J A Veltman1, B C J Hamel1, B B A de Vries1, H van Bokhoven1, H G Yntema1 1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands; 3Center for Human Genetics, University of Leuven, Leuven, Belgium; 4Max Planck Institute for Molecular Genetics, Berlin, Germany; 5INSERM 129-ICGM, Faculté de Médecine Cochin, Paris, France; 6Service de Génétique et INSERM U316, Hôpital Bretonneau, Tours, France; 7 GOLD Program, Hunter Genetics, University of Newcastle, Callaghan, New South Wales 2308, Australia http://jmg.bmj.com/ Corresponding author: on October 2, 2021 by guest. Protected copyright. Helger G. Yntema, PhD Department of Human Genetics Radboud University Nijmegen Medical Centre P.O. Box 9101 6500 HB Nijmegen The Netherlands E-mail: [email protected] tel: +31-24-3613799 fax: +31-24-3616658 1 Copyright Article author (or their employer) 2005. Produced by BMJ Publishing Group Ltd under licence. J Med Genet: first published as 10.1136/jmg.2005.036178 on 16 September 2005. Downloaded from ABSTRACT Introduction: Several studies have shown that array based comparative genomic hybridization (array CGH) is a powerful tool for the detection of copy number changes in the genome of individuals with a congenital disorder.
  • The Cryoelectron Microscopy Structure of the Human CDK-Activating Kinase

    The Cryoelectron Microscopy Structure of the Human CDK-Activating Kinase

    The cryoelectron microscopy structure of the human CDK-activating kinase Basil J. Grebera,b,1,2, Juan M. Perez-Bertoldic, Kif Limd, Anthony T. Iavaronee, Daniel B. Tosoa, and Eva Nogalesa,b,d,f,2 aCalifornia Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720; bMolecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; cBiophysics Graduate Group, University of California, Berkeley, CA 94720; dDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; eQB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, CA 94720; and fHoward Hughes Medical Institute, University of California, Berkeley, CA 94720 Edited by Seth A. Darst, Rockefeller University, New York, NY, and approved August 4, 2020 (received for review May 14, 2020) The human CDK-activating kinase (CAK), a complex composed of phosphoryl transfer (11). However, in addition to cyclin binding, cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical full activation of cell cycle CDKs requires phosphorylation of the regulator of transcription initiation and the cell cycle. It acts by T-loop (9, 12). In animal cells, these activating phosphorylations phosphorylating the C-terminal heptapeptide repeat domain of are carried out by CDK7 (13, 14), itself a cyclin-dependent ki- the RNA polymerase II (Pol II) subunit RPB1, which is an important nase whose activity depends on cyclin H (14). regulatory event in transcription initiation by Pol II, and it phos- In human and other metazoan cells, regulation of transcription phorylates the regulatory T-loop of CDKs that control cell cycle initiation by phosphorylation of the Pol II-CTD and phosphor- progression.
  • Molecular Basis for the Distinct Cellular Functions of the Lsm1-7 and Lsm2-8 Complexes

    Molecular Basis for the Distinct Cellular Functions of the Lsm1-7 and Lsm2-8 Complexes

    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.22.055376; this version posted April 23, 2020. 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. Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes Eric J. Montemayor1,2, Johanna M. Virta1, Samuel M. Hayes1, Yuichiro Nomura1, David A. Brow2, Samuel E. Butcher1 1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. 2Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Correspondence should be addressed to E.J.M. ([email protected]) and S.E.B. ([email protected]). Abstract Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2′,3′ cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines.
  • Redesign of Extensive Protein–DNA Interfaces of Meganucleases Using Iterative Cycles of in Vitro Compartmentalization

    Redesign of Extensive Protein–DNA Interfaces of Meganucleases Using Iterative Cycles of in Vitro Compartmentalization

    Redesign of extensive protein–DNA interfaces of meganucleases using iterative cycles of in vitro compartmentalization Ryo Takeuchi, Michael Choi, and Barry L. Stoddard1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 Edited by David Baker, University of Washington, Seattle, WA, and approved February 13, 2014 (received for review November 8, 2013) LAGLIDADG homing endonucleases (meganucleases) are sequence- residues. Although an industrial-scale engineering pipeline for specific DNA cleavage enzymes used for genome engineering. altering meganuclease specificity has been developed (6), the Recently, meganucleases fused to transcription activator-like effec- specialized knowledge and technology required for that ap- tors have been demonstrated to efficiently introduce targeted proach generally precludes their use by academic laboratories. genome modifications. However, retargeting meganucleases to In addition, a recent study has demonstrated that MegaTALs genomic sequences of interest remains challenging because it usu- (fusions of TAL effector DNA binding regions to meganucleases) ally requires extensive alteration of a large number of amino acid can induce a high level of targeted gene modification in human residues that are situated in and near the DNA interface. Here we cells (21). However, the utility of this platform still depends upon describe an effective strategy to extensively redesign such an the development of efficient strategies to engineer meganucleases extensive biomolecular interface.
  • Gene Expression Profile of THZ1-Treated Nasopharyngeal Carcinoma Cell Lines Indicates Its Involvement in the Inhibition of the Cell Cycle

    Gene Expression Profile of THZ1-Treated Nasopharyngeal Carcinoma Cell Lines Indicates Its Involvement in the Inhibition of the Cell Cycle

    460 Original Article Gene expression profile of THZ1-treated nasopharyngeal carcinoma cell lines indicates its involvement in the inhibition of the cell cycle Lijuan Gao1,2,3#, Shuang Xia4#, Kunyi Zhang1,2,3#, Chengguang Lin1,2,3, Xuyu He4, Ying Zhang4 1Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China; 3Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China; 4Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China Contributions: (I) Conception and design: L Gao, S Xia, K Zhang; (II) Administrative support: X He, Y Zhang; (III) Provision of study materials or patients: L Gao, S Xia, K Zhang; (IV) Collection and assembly of data: C Lin; (V) Data analysis and interpretation: C Lin, X He, Y Zhang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #The authors contributed equally to this work. Correspondence to: Xuyu He; Ying Zhang. Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd road, Guangzhou 510080, China. Email: [email protected]; [email protected]. Background: The aim of this study was to identify downstream target genes and pathways regulated by THZ1 in nasopharyngeal carcinoma (NPC). Methods: The gene expression profile of GSE95750 in two NPC cell lines, untreated group and treated with THZ1 group, was analyzed.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    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.
  • Supplementary Table 3 Complete List of RNA-Sequencing Analysis of Gene Expression Changed by ≥ Tenfold Between Xenograft and Cells Cultured in 10%O2

    Supplementary Table 3 Complete List of RNA-Sequencing Analysis of Gene Expression Changed by ≥ Tenfold Between Xenograft and Cells Cultured in 10%O2

    Supplementary Table 3 Complete list of RNA-Sequencing analysis of gene expression changed by ≥ tenfold between xenograft and cells cultured in 10%O2 Expr Log2 Ratio Symbol Entrez Gene Name (culture/xenograft) -7.182 PGM5 phosphoglucomutase 5 -6.883 GPBAR1 G protein-coupled bile acid receptor 1 -6.683 CPVL carboxypeptidase, vitellogenic like -6.398 MTMR9LP myotubularin related protein 9-like, pseudogene -6.131 SCN7A sodium voltage-gated channel alpha subunit 7 -6.115 POPDC2 popeye domain containing 2 -6.014 LGI1 leucine rich glioma inactivated 1 -5.86 SCN1A sodium voltage-gated channel alpha subunit 1 -5.713 C6 complement C6 -5.365 ANGPTL1 angiopoietin like 1 -5.327 TNN tenascin N -5.228 DHRS2 dehydrogenase/reductase 2 leucine rich repeat and fibronectin type III domain -5.115 LRFN2 containing 2 -5.076 FOXO6 forkhead box O6 -5.035 ETNPPL ethanolamine-phosphate phospho-lyase -4.993 MYO15A myosin XVA -4.972 IGF1 insulin like growth factor 1 -4.956 DLG2 discs large MAGUK scaffold protein 2 -4.86 SCML4 sex comb on midleg like 4 (Drosophila) Src homology 2 domain containing transforming -4.816 SHD protein D -4.764 PLP1 proteolipid protein 1 -4.764 TSPAN32 tetraspanin 32 -4.713 N4BP3 NEDD4 binding protein 3 -4.705 MYOC myocilin -4.646 CLEC3B C-type lectin domain family 3 member B -4.646 C7 complement C7 -4.62 TGM2 transglutaminase 2 -4.562 COL9A1 collagen type IX alpha 1 chain -4.55 SOSTDC1 sclerostin domain containing 1 -4.55 OGN osteoglycin -4.505 DAPL1 death associated protein like 1 -4.491 C10orf105 chromosome 10 open reading frame 105 -4.491
  • Ageing-Associated Changes in DNA Methylation in X and Y Chromosomes

    Ageing-Associated Changes in DNA Methylation in X and Y Chromosomes

    Kananen and Marttila Epigenetics & Chromatin (2021) 14:33 Epigenetics & Chromatin https://doi.org/10.1186/s13072-021-00407-6 RESEARCH Open Access Ageing-associated changes in DNA methylation in X and Y chromosomes Laura Kananen1,2,3,4* and Saara Marttila4,5* Abstract Background: Ageing displays clear sexual dimorphism, evident in both morbidity and mortality. Ageing is also asso- ciated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. Here, we sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14–92 years. Results: In total, we identifed 46 age-associated CpG sites in the male Y, 1327 age-associated CpG sites in the male X, and 325 age-associated CpG sites in the female X. The X chromosomal age-associated CpGs showed signifcant overlap between females and males, with 122 CpGs identifed as age-associated in both sexes. Age-associated X chro- mosomal CpGs in both sexes were enriched in CpG islands and depleted from gene bodies and showed no strong trend towards hypermethylation nor hypomethylation. In contrast, the Y chromosomal age-associated CpGs were enriched in gene bodies, and showed a clear trend towards hypermethylation with age. Conclusions: Signifcant overlap in X chromosomal age-associated CpGs identifed in males and females and their shared features suggest that despite the uneven chromosomal dosage, diferences in ageing-associated DNA methylation changes in the X chromosome are unlikely to be a major contributor of sex dimorphism in ageing.
  • Cytotoxic Effects and Changes in Gene Expression Profile

    Cytotoxic Effects and Changes in Gene Expression Profile

    Toxicology in Vitro 34 (2016) 309–320 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile Martina Jonsson a,⁎,MarikaJestoib, Minna Anthoni a, Annikki Welling a, Iida Loivamaa a, Ville Hallikainen c, Matti Kankainen d, Erik Lysøe e, Pertti Koivisto a, Kimmo Peltonen a,f a Chemistry and Toxicology Research Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, Finland b Product Safety Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, c The Finnish Forest Research Institute, Rovaniemi Unit, P.O. Box 16, FI-96301 Rovaniemi, Finland d Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FI-00014, Finland e Plant Health and Biotechnology, Norwegian Institute of Bioeconomy, Høyskoleveien 7, NO -1430 Ås, Norway f Finnish Safety and Chemicals Agency (Tukes), Opastinsilta 12 B, FI-00521 Helsinki, Finland article info abstract Article history: The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium,isprevalentin Received 3 December 2015 grains and grain-based products in different geographical areas. Although enniatins have not been associated Received in revised form 5 April 2016 with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects Accepted 28 April 2016 of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of ap- Available online 6 May 2016 optosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome ex- fi Keywords: pression pro ling of exposed rat primary hepatocytes.
  • Biology Assessment Plan Spring 2019

    Biology Assessment Plan Spring 2019

    Biological Sciences Department 1 Biology Assessment Plan Spring 2019 Task: Revise the Biology Program Assessment plans with the goal of developing a sustainable continuous improvement plan. In order to revise the program assessment plan, we have been asked by the university assessment committee to revise our Students Learning Outcomes (SLOs) and Program Learning Outcomes (PLOs). Proposed revisions Approach: A large community of biology educators have converged on a set of core biological concepts with five core concepts that all biology majors should master by graduation, namely 1) evolution; 2) structure and function; 3) information flow, exchange, and storage; 4) pathways and transformations of energy and matter; and (5) systems (Vision and Change, AAAS, 2011). Aligning our student learning and program goals with Vision and Change (V&C) provides many advantages. For example, the V&C community has recently published a programmatic assessment to measure student understanding of vision and change core concepts across general biology programs (Couch et al. 2019). They have also carefully outlined student learning conceptual elements (see Appendix A). Using the proposed assessment will allow us to compare our student learning profiles to those of similar institutions across the country. Revised Student Learning Objectives SLO 1. Students will demonstrate an understanding of core concepts spanning scales from molecules to ecosystems, by analyzing biological scenarios and data from scientific studies. Students will correctly identify and explain the core biological concepts involved relative to: biological evolution, structure and function, information flow, exchange, and storage, the pathways and transformations of energy and matter, and biological systems. More detailed statements of the conceptual elements students need to master are presented in appendix A.