DOCSLIB.ORG

Genetic Mechanisms Behind Cell Specification in the Drosophila CNS

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Mechanisms Behind Cell Specification in the Drosophila CNS Linköping University Medical Dissertations No. 1157 Genetic mechanisms behind cell specification in the Drosophila CNS Magnus Baumgardt Department of Clinical and Experimental Medicine Linköping University, Sweden Linköping 2009 During the course of the research underlying this thesis, Magnus Baumgardt was enrolled in Forum Scientium, a multidisciplinary doctoral programme at Linköping University, Sweden. Magnus Baumgardt, 2009 Cover picture/illustration: An Apterous cluster, stained for Apterous (green), Nplp1 (red), and FMRFa (blue). Published articles have been reprinted with the permission of the copyright holder. Printed in Sweden by LiU-Tryck, Linköping, Sweden, 2009 ISBN 978-91-7393-483-1 ISSN 0345-0082 “Science is built up of facts, as a house is built of stones; but an accumulation of facts is no more a science than a heap of stones is a house.” Henri Poincaré, Science and Hypothesis, 1905 CONTENTS LIST OF PAPERS ..................................................................................... 1 ABBREVIATIONS .................................................................................... 3 ABSTRACT .............................................................................................. 5 INTRODUCTION ..................................................................................... 7 The fundamental questions of developmental neurobiology .............. 7 Evolution, structure and function of the CNS ..................................... 9 The cells of the nervous system: neurons and glia ........................................... 9 Nervous system architecture ............................................................................ 10 The evolution of the nervous system ................................................................ 12 The CNS of Drosophila melanogaster .............................................................. 12 The development of the CNS .............................................................14 Axes formation and the specification of the neuroectoderm........................... 15 Patterning of the neuroectoderm ..................................................................... 18 Lineage in the Drosophila CNS ....................................................................... 29 Lineage in the vertebrate CNS......................................................................... 36 The Drosophila temporal gene cascade .......................................................... 40 Temporal specification of vertebrate neural progenitors ............................... 47 Terminal cell fate specification ....................................................................... 50 The Ap neuron model ...................................................................... 58 AIMS ..................................................................................................... 69 MATERIALS AND METHODS ................................................................. 71 RESULTS AND DISCUSSION ................................................................. 73 Paper I............................................................................................. 73 Paper II ............................................................................................ 77 Paper III .......................................................................................... 80 Paper IV .......................................................................................... 85 IDENTIFIED MECHANISMS ................................................................. 89 FUTURE CHALLENGES ........................................................................ 93 ACKNOWLEDGEMENTS ....................................................................... 95 REFERENCES ....................................................................................... 97 List of papers LIST OF PAPERS This thesis is based upon the following papers, which are referred to in the text by their roman numerals: PAPER I Baumgardt M, Miguel-Aliaga I, Karlsson D, Ekman H, and Thor S. (2007). Specification of Neuronal Identities by Feedforward Combinatorial Coding. PLoS Biology 5(2):e37. PAPER II Baumgardt M, Karlsson D, Terriente J, Díaz-Benjumea FJ, and Thor S. Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops. Cell, in press. PAPER III Karlsson D, Baumgardt M, and Thor S. Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues. Submitted. PAPER IV Benito-Sipos J, Estacio A, Moris M, Baumgardt M, Thor S, and Díaz-Benjumea FJ. A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS. Manuscript. 1 2 Abbreviations ABBREVIATIONS CNS Central nervous system VNC Ventral nerve cord NB Neuroblast GMC Ganglion mother cell A-P Anterior-Posterior D-V Dorsal-Ventral HD Homeodomain LIM-HD LIM-homeodomain bHLH Basic helix-loop-helix ISN Intersegmental nerve SN Segmental nerve TN Transverse nerve MMC Medial motor column LMC Lateral motor column PGC Pre-ganglionic chain FFL Feed-forward loop 3 4 Abstract ABSTRACT The human central nervous system (CNS) contains a daunting number of cells and tremendous cellular diversity. A fundamental challenge of developmental neurobiology is to address the questions of how so many different types of neurons and glia can be generated at the precise time and place, making precisely the right connections. Resolving this issue involves dissecting the elaborate genetic networks that act within neurons and glia, as well as in the neural progenitor cells that generates them, to specify their identities. My PhD project has involved addressing a number of unresolved issues pertaining to how neural progenitor cells are specified to generate different types of neurons and glial cells in different temporal and spatial domains, and also how these early temporal and spatial cues are integrated to activate late cell fate determinants, which act in post-mitotic neural cells to activate distinct batteries of terminal differentiation genes. Analyzing the development of a specific Drosophila melanogaster (Drosophila) CNS stem cell – the neuroblast 5-6 (NB5-6) – we have identified several novel mechanisms of cell fate specification in the Drosophila CNS. We find that, within this lineage, the differential specification of a group of sequentially generated neurons – the Ap cluster neurons – is critically dependent upon the simultaneous triggering of two opposing feed-forward loops (FFLs) within the neuroblast. The first FFL involves cell fate determinants and progresses within the post-mitotic neurons to establish a highly specific combinatorial code of regulators, which activates a distinct battery of terminal differentiation genes. The second loop, which progresses in the neuroblast, involves temporal and sub-temporal genes that together oppose the progression of the first FFL. This leads to the establishment of an alternative code of regulators in late-born Ap cluster neurons, whereby alternative cell fates are specified. Furthermore, we find that the generation and specification of the Ap cluster neurons is modulated along the neuraxis by two different mechanisms. In abdominal segments, Hox genes of the Bithorax cluster integrates with Pbx/Meis factors to instruct NB5-6 to leave the cell cycle before the Ap cluster neurons are generated. In brain segments, Ap cluster neuron equivalents are generated, but improperly specified due to the absence of the proper Hox and temporal code. Additionally, in thoracic segments we find that the specification of the Ap cluster neurons is critically dependent upon the integration of the Hox, Pbx/Meis, and the temporal genes, in the activation of the critical cell fate determinant FFL. We speculate that the developmental principles of (i) feed-forward combinatorial coding; (ii) simultaneously triggered yet opposing feed-forward loops; and (iii) integration of different Hox, Pbx/Meis, and temporal factors, at different axial levels to control inter-segmental differences in lineage progression and specification; might be used widely throughout the animal kingdom to generate cell type diversity in the CNS. 5 6 Introduction INTRODUCTION The fundamental questions of developmental neurobiology Developmental biology is the study of the processes by which a multicellular organism develops from one cell, into an adult. However, most multicellular organisms continue development, in a sense, even as adults, as old or injured cells constantly need to be replaced by new ones, making also these processes an intricate part of the field of developmental biology. In essence developmental biologists aim to answer the same questions, and solve the same problems, as nature itself had to solve some 2 billion years ago as true multicellularity evolved. This transition posed several challenges for the ancient organisms. The most fundamental of these challenges was how the initial cell mass of the organism - commonly only one cell, a zygote – could propagate in such a way that the cells it generated became differentially specified to perform various specialized functions within the organism, while their proliferation and integration was still controlled in a precise enough manner to allow for a fully functional final structure. In no other area of developmental biology are the questions of how cells are precisely generated, specified, and integrated, as challenging as in the study of the animal central nervous system (CNS).
Load more

Recommended publications
  • Conservation and Diversification of Appendage Identity Specification Mechanisms Along the Anteroposterior and Proximodistal Axes in Panarthropoda Frank W
    University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 8-23-2013 Conservation and Diversification of Appendage Identity Specification Mechanisms Along the Anteroposterior and Proximodistal Axes in Panarthropoda Frank W. Smith III University of Connecticut, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Smith, Frank W. III, "Conservation and Diversification of Appendage Identity Specification Mechanisms Along the Anteroposterior and Proximodistal Axes in Panarthropoda" (2013). Doctoral Dissertations. 161. https://opencommons.uconn.edu/dissertations/161 Conservation and Diversification of Appendage Identity Specification Mechanisms Along the Anteroposterior and Proximodistal Axes in Panarthropoda Frank Wesley Smith III, PhD University of Connecticut, 2013 A key characteristic of arthropods is their diverse serially homologous segmented appendages. This dissertation explores diversification of these appendages, and the developmental mechanisms producing them. In Chapter 1, the roles of genes that specify antennal identity in Drosophila melanogaster were investigated in the flour beetle Tribolium castaneum. Antenna-to-leg transformations occurred in response to RNA interference (RNAi) against homothorax, extradenticle, spineless and Distal-less. However, for homothorax/extradenticle RNAi, the extent of transformation along the proximodistal axis differed between embryogenesis and metamorphosis. This suggests that distinct mechanisms specify antennal identity during flour beetle embryogenesis and metamorphosis and leads to a model for the evolution of the Drosophila antennal identity mechanism. Homothorax/Extradenticle acquire many of their identity specification roles by acting as Hox cofactors. In chapter 2, the metamorphic roles of the Hox genes, extradenticle, and homothorax were compared in T. castaneum. homothorax/extradenticle RNAi and Hox RNAi produced similar body wall phenotypes but different appendage phenotypes.
    [Show full text]
  • Role of Notch Signaling in Establishing the Hemilineages of Secondary Neurons in Drosophila Melanogaster James W
    RESEARCH ARTICLE 53 Development 137, 53-61 (2010) doi:10.1242/dev.041749 Role of Notch signaling in establishing the hemilineages of secondary neurons in Drosophila melanogaster James W. Truman*,§, Wanda Moats, Janet Altman*, Elizabeth C. Marin† and Darren W. Williams‡ SUMMARY The secondary neurons generated in the thoracic central nervous system of Drosophila arise from a hemisegmental set of 25 neuronal stem cells, the neuroblasts (NBs). Each NB undergoes repeated asymmetric divisions to produce a series of smaller ganglion mother cells (GMCs), which typically divide once to form two daughter neurons. We find that the two daughters of the GMC consistently have distinct fates. Using both loss-of-function and gain-of-function approaches, we examined the role of Notch signaling in establishing neuronal fates within all of the thoracic secondary lineages. In all cases, the ‘A’ (NotchON) sibling assumes one fate and the ‘B’ (NotchOFF) sibling assumes another, and this relationship holds throughout the neurogenic period, resulting in two major neuronal classes: the A and B hemilineages. Apparent monotypic lineages typically result from the death of one sibling throughout the lineage, resulting in a single, surviving hemilineage. Projection neurons are predominantly from the B hemilineages, whereas local interneurons are typically from A hemilineages. Although sibling fate is dependent on Notch signaling, it is not necessarily dependent on numb, a gene classically involved in biasing Notch activation. When Numb was removed at the start of larval neurogenesis, both A and B hemilineages were still generated, but by the start of the third larval instar, the removal of Numb resulted in all neurons assuming the A fate.
    [Show full text]
  • Olig2 and Ngn2 Function in Opposition to Modulate Gene Expression in Motor Neuron Progenitor Cells
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells Soo-Kyung Lee,1 Bora Lee,1 Esmeralda C. Ruiz, and Samuel L. Pfaff2 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA Spinal motor neurons and oligodendrocytes are generated sequentially from a common pool of progenitors termed pMN cells. Olig2 is a bHLH-class transcription factor in pMN cells, but it has remained unclear how its transcriptional activity is modulated to first produce motor neurons and then oligodendrocytes. Previous studies have shown that Olig2 primes pMN cells to become motor neurons by triggering the expression of Ngn2 and Lhx3. Here we show that Olig2 also antagonizes the premature expression of post-mitotic motor neuron genes in pMN cells. This blockade is counteracted by Ngn2, which accumulates heterogeneously in pMN cells, thereby releasing a subset of the progenitors to differentiate and activate expression of post-mitotic motor neuron genes. The antagonistic relationship between Ngn2 and Olig2 is mediated by protein interactions that squelch activity as well as competition for shared DNA-binding sites. Our data support a model in which the Olig2/Ngn2 ratio in progenitor cells serves as a gate for timing proper gene expression during the development of pMN cells: Olig2high maintains the pMN state, thereby holding cells in reserve for oligodendrocyte generation, whereas Ngn2high favors the conversion of pMN cells into post-mitotic motor neurons. [Keywords: Motor neuron; oligodendrocyte; development; basic helix–loop–helix (bHLH); neurogenin (Ngn); Olig] Supplemental material is available at http://www.genesdev.org.
    [Show full text]
  • Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins
    International Journal of Molecular Sciences Article Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins M. Quadir Siddiqui 1,† , Maulik D. Badmalia 1,† and Trushar R. Patel 1,2,3,* 1 Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada; [email protected] (M.Q.S.); [email protected] (M.D.B.) 2 Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1, Canada 3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada * Correspondence: [email protected] † These authors contributed equally to the work. Abstract: Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and func- tions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share Citation: Siddiqui, M.Q.; Badmalia, similarities with transcriptional regulators and have positively charged electrostatic patches, which M.D.; Patel, T.R.
    [Show full text]
  • Genesis and Migration 3
    Genesis and migration 3 Chapter 3 Outline precursor, and it appears that the information to define a given type of cell resides largely in factors derived directly from the What determines the number of cells produced by the precursors. The same is true for the neuroblasts that produce progenitors? 52 the Drosophila central nervous system: the production of neu- rons from the neuroblasts is highly stereotypic. The neuroblasts The generation of neurons and glia 55 of the insect CNS delaminate from the ventral–lateral ecto- Cerebral cortex histogenesis 58 derm neurogenic region in successive waves (see Chapter 1). Cerebellar cortex histogenesis 63 In Drosophila, about 25 neuroblasts delaminate in each seg- ment, and they are organized in four columns and six rows (Doe Molecular mechanisms of neuronal migration 65 and Smouse, 1990). Once the neuroblast segregates from the Postembryonic and adult neurogenesis 67 ectoderm, it undergoes several asymmetric divisions, giving Summary 73 rise to approximately five smaller ganglion mother cells. Each ganglion mother cell then divides to generate a pair of neurons. References 73 These neurons make up the segmental ganglia of the ventral nerve cord and have stereotypic numbers and types of neurons. In the vertebrate, the situation gets considerably more com- The human brain is made up of approximately 100 billion plex. The neural tube of most vertebrates is initially a single neurons and even more glial cells. The sources of all these layer thick. As neurogenesis proceeds, the progenitor cells neurons and glia are the cells of the neural tube, described undergo a large number of cell divisions to produce a much in the previous chapters.
    [Show full text]
  • The NOTCH4-HEY1 Pathway Induces Epithelial Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma
    Author Manuscript Published OnlineFirst on November 16, 2017; DOI: 10.1158/1078-0432.CCR-17-1366 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The NOTCH4-HEY1 pathway induces epithelial mesenchymal transition in head and neck squamous cell carcinoma Authors: Takahito Fukusumi1, Theresa W Guo2, Akihiro Sakai1, Mizuo Ando1, Shuling Ren1, Sunny Haft1, Chao Liu1, Panomwat Amornphimoltham1, J. Silvio Gutkind1, Joseph A Califano1 1 Moores Cancer Center, University of California San Diego, 3855 Health Science Drive, MC 0803 La Jolla, California 92093, U.S.A. 2 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21231, U.S.A. Running Title: NOTCH4-HEY1 induces EMT in HNSCC Key Words: Head and neck squamous cell carcinoma, TCGA, NOTCH4, HEY1, EMT Financial Support This study was supported by National Institute of Dental and Craniofacial Research (NIDCR, number: R01DE023347). J.A.Califano received this grant. Correspondence: Joseph A. Califano, MD, Department of Otolaryngology - Head and Neck Surgery, University of California San Diego, 3855 Health Science Drive, MC 0803 La Jolla, California 92093, U.S.A. Phone: 619-543-7895; E-mail; [email protected] Disclosure of Potential Conflict of Interest The authors declare no potential conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 16, 2017; DOI: 10.1158/1078-0432.CCR-17-1366 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Background: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases.
    [Show full text]
  • The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid
    The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome Annette K. Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik and Øystein Bruserud Supplementary Material S2 of S31 Table S1. Detailed information about the 68 AML patients included in the study. # of blasts Viability Proliferation Cytokine Viable cells Change in ID Gender Age Etiology FAB Cytogenetics Mutations CD34 Colonies (109/L) (%) 48 h (cpm) secretion (106) 5 weeks phenotype 1 M 42 de novo 241 M2 normal Flt3 pos 31.0 3848 low 0.24 7 yes 2 M 82 MF 12.4 M2 t(9;22) wt pos 81.6 74,686 low 1.43 969 yes 3 F 49 CML/relapse 149 M2 complex n.d. pos 26.2 3472 low 0.08 n.d. no 4 M 33 de novo 62.0 M2 normal wt pos 67.5 6206 low 0.08 6.5 no 5 M 71 relapse 91.0 M4 normal NPM1 pos 63.5 21,331 low 0.17 n.d. yes 6 M 83 de novo 109 M1 n.d. wt pos 19.1 8764 low 1.65 693 no 7 F 77 MDS 26.4 M1 normal wt pos 89.4 53,799 high 3.43 2746 no 8 M 46 de novo 26.9 M1 normal NPM1 n.d. n.d. 3472 low 1.56 n.d. no 9 M 68 MF 50.8 M4 normal D835 pos 69.4 1640 low 0.08 n.d.
    [Show full text]
  • Function and Specificity of Synthetic Hox Transcription Factors in Vivo
    Function and specificity of synthetic Hox transcription factors in vivo Dimitrios K. Papadopoulosa, Vladana Vukojevićb, Yoshitsugu Adachic, Lars Tereniusb, Rudolf Riglerd,e, and Walter J. Gehringa,1 aDepartment of Cell Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; bDepartment of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden; cDepartment of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom; dDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; and eLaboratory of Biomedical Optics, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland Contributed by Walter J. Gehring, December 23, 2009 (sent for review November 3, 2009) Homeotic (Hox) genes encode transcription factors that confer Bric-à-Brac interacting protein 2 (Bip2) (17). However, Hox segmental identity along the anteroposterior axis of the embryo. cofactors do not suffice to entirely explain Hox specificity. The However the molecular mechanisms underlying Hox-mediated finding of cofactor independent Hox function (18) contributed transcription and the differential requirements for specificity in to the realization that further sequences residing in the N terminus the regulation of the vast number of Hox-target genes remain of Hox proteins might be the link for increased specificity in vivo. ill-defined. Here we show that synthetic Sex combs reduced In the present work we have derived synthetic Scr genes
    [Show full text]
  • Drosophila Mef2 Is Essential for Normal Mushroom Body and Wing Development
    bioRxiv preprint doi: https://doi.org/10.1101/311845; this version posted April 30, 2018. 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. Drosophila mef2 is essential for normal mushroom body and wing development Jill R. Crittenden1, Efthimios M. C. Skoulakis2, Elliott. S. Goldstein3, and Ronald L. Davis4 1McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 2Division of Neuroscience, Biomedical Sciences Research Centre "Alexander Fleming", Vari, 16672, Greece 3 School of Life Science, Arizona State University, Tempe, AZ, 85287, USA 4Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA Key words: MEF2, mushroom bodies, brain, muscle, wing, vein, Drosophila 1 bioRxiv preprint doi: https://doi.org/10.1101/311845; this version posted April 30, 2018. 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. ABSTRACT MEF2 (myocyte enhancer factor 2) transcription factors are found in the brain and muscle of insects and vertebrates and are essential for the differentiation of multiple cell types. We show that in the fruitfly Drosophila, MEF2 is essential for normal development of wing veins, and for mushroom body formation in the brain. In embryos mutant for D-mef2, there was a striking reduction in the number of mushroom body neurons and their axon bundles were not detectable.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • Accompanies CD8 T Cell Effector Function Global DNA Methylation
    Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer, Benjamin G. Barwick, Benjamin A. Youngblood, Rafi Ahmed and Jeremy M. Boss This information is current as of October 1, 2021. J Immunol 2013; 191:3419-3429; Prepublished online 16 August 2013; doi: 10.4049/jimmunol.1301395 http://www.jimmunol.org/content/191/6/3419 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130139 Material 5.DC1 References This article cites 81 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/191/6/3419.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function Christopher D. Scharer,* Benjamin G. Barwick,* Benjamin A. Youngblood,*,† Rafi Ahmed,*,† and Jeremy M.
    [Show full text]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]