DOCSLIB.ORG

Stony Brook University

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Stony Brook University SSStttooonnnyyy BBBrrrooooookkk UUUnnniiivvveeerrrsssiiitttyyy The official electronic file of this thesis or dissertation is maintained by the University Libraries on behalf of The Graduate School at Stony Brook University. ©©© AAAllllll RRRiiiggghhhtttsss RRReeessseeerrrvvveeeddd bbbyyy AAAuuuttthhhooorrr... Mechanistic evaluation of NSD3 in the pathogenesis of acute myeloid leukemia A Dissertation Presented by Chen Shen to The Graduate School in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Molecular and Cellular Biology Stony Brook University May 2016 Stony Brook University The Graduate School Chen Shen We, the dissertation committee for the above candidate for the Doctor of Philosophy degree, hereby recommend acceptance of this dissertation. Dr. Christopher R. Vakoc– Dissertation Advisor Associate Professor, Cold Spring Harbor Laboratory Dr. Alea A. Mills - Chairperson of Defense Professor, Cold Spring Harbor Laboratory Dr. Adrian R. Krainer Professor, Cold Spring Harbor Laboratory Dr. Lloyd C. Trotman Associate Professor, Cold Spring Harbor Laboratory Dr. Ed Luk Assistant Professor, Department of Biochemistry and Cell Biology, Stony Brook University Dr. Christopher M. Hammell Assistant Professor, Cold Spring Harbor Laboratory This dissertation is accepted by the Graduate School Charles Taber Dean of the Graduate School ii Abstract of the Dissertation Mechanistic evaluation of NSD3 in the pathogenesis of acute myeloid leukemia by Chen Shen Doctor of Philosophy in Molecular and Cellular Biology Stony Brook University 2016 The bromodomain and extra-terminal (BET) protein BRD4 is a validated drug target in hematological malignancies, owing to its essential role in sustaining oncogenic transcriptional programs. To gain insight into the cancer-relevant mechanistic function of BRD4, I have investigated its mechanism of transcriptional activation in the MLL-fusion subtype of acute myeloid leukemia (AML) with experimental approaches including small hairpin RNA (shRNA) knockdown, clustered regularly-interspaced short palindromic repeats (CRISPR)-Cas9 knockout, biochemistry, RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq). In this study, I demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. I show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by utilizing a Pro-Trp-Trp-Pro (PWWP) module, and by employing an acidic transactivation domain. Phenotypic and transcriptional effects of genetic targeting of NSD3 or CHD8 mimic the effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome and are each released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4- NSD3-CHD8 complexes from chromatin to suppress transcription. iii Dedication Page I sincerely dedicate this thesis to my beloved family, dear teachers and friends. iv Table of Contents List of Figures .............................................................................................................................. viii List of Tables .................................................................................................................................. x List of Abbreviations ..................................................................................................................... xi Acknowledgments........................................................................................................................ xiii Chapter 1: Introduction ................................................................................................................... 1 1.1 Acute myeloid leukemia ....................................................................................................... 1 1.1.1 Epidemiology and symptoms of acute myeloid leukemia ............................................. 1 1.1.2 Genetics of AML ........................................................................................................... 2 1.1.3 Classifications and diagnosis of AML ........................................................................... 2 1.1.4 Current therapies for AML patients ............................................................................... 3 1.2 BRD4 and BET inhibitors ..................................................................................................... 6 1.2.1 Basic mechanism of BRD4 functions ............................................................................ 6 1.2.2 Direct BRD4 interaction with transcription factors ....................................................... 8 1.2.3 BET inhibitors .............................................................................................................. 11 1.2.4 Therapeutic targeting of BRD4 with small molecules ................................................. 12 1.3 A uncharacterized NSD family protein NSD3.................................................................... 21 Chapter 2: A Short Isoform of NSD3 Lacking Catalytic Function Is Essential in Acute Myeloid Leukemia....................................................................................................................................... 24 2.1 NSD3 is required for AML cell proliferation ..................................................................... 26 2.2 NSD3 is required for maintaining the undifferentiated state of AML cells ....................... 30 2.3 c-Myc is an essential target gene of NSD3 in AML maintenance ...................................... 30 2.4 NSD3 regulates a similar global gene profile with BRD4 in AML .................................... 33 2.5 A short isoform of NSD3 is essential in AML ................................................................... 35 Chapter 3: NSD3-short Binds Directly to the BRD4 ET Domain ................................................ 39 3.1 NSD3 is an ET-domain associated protein ......................................................................... 39 3.2 NSD3-short 100-263 is a BRD4 interacting domain .......................................................... 41 3.3 NSD3-short 100-263 Binds BRD4 ET-domain directly ..................................................... 44 3.4 Dissociation of NSD3 from BRD4 impairs ET domain functions ..................................... 46 v Chapter 4: NSD3-short Is an Adaptor Protein that Links BRD4 to the CHD8 Chromatin Remodeling Enzyme ..................................................................................................................... 50 4.1 CHD8 is required for AML cell proliferation ..................................................................... 50 4.2 CHD8 is required for maintaining the undifferentiated state of AML cells ....................... 56 4.3 CHD8 regulates a similar global gene profile with NSD3 and BRD4 in AML ................. 58 4.4 NSD3-short bridges BRD4 to the CHD8 chromatin remodeler ......................................... 60 Chapter 5: BRD4 Recruits NSD3 and CHD8 to Super-Enhancer Regions at Oncogene Loci ..... 62 5.1 BRD4, NSD3, and CHD8 colocalize at active promoters and enhancers across the AML genome ...................................................................................................................................... 62 5.2 BRD4 recruits NSD3 and CHD8 to the Myc +1.7 Mb super-enhancer region ................... 66 Chapter 6: NSD3-short Uses Four Distinct Interaction Surfaces to Sustain AML Cell Proliferation .................................................................................................................................. 71 6.1 NSD3-short uses a PWWP reader module to sustain AML cell proliferation .................... 71 6.2 NSD3-short possesses an acidic transactivation domain .................................................... 76 6.3 CRISPR-Cas9 scanning of exons encoding NSD3-short in AML...................................... 78 Chapter 7: Conclusions and Perspectives ..................................................................................... 82 7.1 Summary ............................................................................................................................. 82 7.2 Discussions ......................................................................................................................... 84 7.2.1 BRD4 in AML maintenance ........................................................................................ 84 7.2.2 Functions of the PWWP domain in NSD3-short ......................................................... 86 7.2.3 Functions of NSD3-long .............................................................................................. 87 7.2.4 Interactions between NSD3 and BET family proteins other than BRD4 .................... 87 7.3 Perspectives and future directions ...................................................................................... 88 Chapter 8: Extended Materials and Methods ................................................................................ 91 8.1 Cell culture .......................................................................................................................... 91 8.2 Cell lines and plasmids
Load more

Recommended publications
  • Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers
    Identification and Characterization of TPRKB Dependency in TP53 Deficient Cancers. by Kelly Kennaley A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Cellular Pathology) in the University of Michigan 2019 Doctoral Committee: Associate Professor Zaneta Nikolovska-Coleska, Co-Chair Adjunct Associate Professor Scott A. Tomlins, Co-Chair Associate Professor Eric R. Fearon Associate Professor Alexey I. Nesvizhskii Kelly R. Kennaley [email protected] ORCID iD: 0000-0003-2439-9020 © Kelly R. Kennaley 2019 Acknowledgements I have immeasurable gratitude for the unwavering support and guidance I received throughout my dissertation. First and foremost, I would like to thank my thesis advisor and mentor Dr. Scott Tomlins for entrusting me with a challenging, interesting, and impactful project. He taught me how to drive a project forward through set-backs, ask the important questions, and always consider the impact of my work. I’m truly appreciative for his commitment to ensuring that I would get the most from my graduate education. I am also grateful to the many members of the Tomlins lab that made it the supportive, collaborative, and educational environment that it was. I would like to give special thanks to those I’ve worked closely with on this project, particularly Dr. Moloy Goswami for his mentorship, Lei Lucy Wang, Dr. Sumin Han, and undergraduate students Bhavneet Singh, Travis Weiss, and Myles Barlow. I am also grateful for the support of my thesis committee, Dr. Eric Fearon, Dr. Alexey Nesvizhskii, and my co-mentor Dr. Zaneta Nikolovska-Coleska, who have offered guidance and critical evaluation since project inception.
    [Show full text]
  • Supporting Information
    Supporting Information Figure S1. The functionality of the tagged Arp6 and Swr1 was confirmed by monitoring cell growth and sensitivity to hydeoxyurea (HU). Five-fold serial dilutions of each strain were plated on YPD with or without 50 mM HU and incubated at 30°C or 37°C for 3 days. Figure S2. Localization of Arp6 and Swr1 on chromosome 3. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 3L, Tel 3R, CEN3, and the RP gene are shown under the panels. Figure S3. Localization of Arp6 and Swr1 on chromosome 4. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) in the whole chromosome region are compared. The position of Tel 4L, Tel 4R, CEN4, SWR1, and RP genes are shown under the panels. Figure S4. Localization of Arp6 and Swr1 on the region including the SWR1 gene of chromosome 4. The binding of Arp6- FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position and orientation of the SWR1 gene is shown. Figure S5. Localization of Arp6 and Swr1 on chromosome 5. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 5L, Tel 5R, CEN5, and the RP genes are shown under the panels. Figure S6. Preferential localization of Arp6 and Swr1 in the 5′ end of genes. Vertical bars represent the binding ratio of proteins in each locus.
    [Show full text]
  • Spatial Protein Interaction Networks of the Intrinsically Disordered Transcription Factor C(%3$
    Spatial protein interaction networks of the intrinsically disordered transcription factor C(%3$ Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) im Fach Biologie/Molekularbiologie eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin Von Evelyn Ramberger, M.Sc. Präsidentin der Humboldt-Universität zu Berlin Prof. Dr.-Ing.Dr. Sabine Kunst Dekan der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin Prof. Dr. Bernhard Grimm Gutachter: 1. Prof. Dr. Achim Leutz 2. Prof. Dr. Matthias Selbach 3. Prof. Dr. Gunnar Dittmar Tag der mündlichen Prüfung: 12.8.2020 For T. Table of Contents Selbstständigkeitserklärung ....................................................................................1 List of Figures ............................................................................................................2 List of Tables ..............................................................................................................3 Abbreviations .............................................................................................................4 Zusammenfassung ....................................................................................................6 Summary ....................................................................................................................7 1. Introduction ............................................................................................................8 1.1. Disordered proteins
    [Show full text]
  • Regulation of Cat-1 Gene Transcription During Physiological
    REGULATION OF CAT-1 GENE TRANSCRIPTION DURING PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS by CHARLIE HUANG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Maria Hatzoglou Department of Nutrition CASE WESTERN RESERVE UNIVERSITY MAY 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. This workis dedicated to my parents (DICK and MEI-HUI), brother (STEVE), and sister (ANGELA) for their love and support during my graduate study. iii TABLE OF CONTENTS Dedication iii Table of Contents iv List of Tables vii List of Figures viii Acknowledgements ix List of Abbreviations xi Abstract xv CHAPTER 1: INTRODUCTION Amino acids and amino acid transporters 1 System y+ transporters 2 Physiological significance of Cat-1 6 Gene transcription in eukaryotic cells 7 Cat-1 gene structure 10 Regulation of Cat-1 expression 11 The Unfolded Protein Response (UPR) and Cat-1 expression 14
    [Show full text]
  • SUMO and Transcriptional Regulation: the Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies
    molecules Review SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies Mathias Boulanger 1,2 , Mehuli Chakraborty 1,2, Denis Tempé 1,2, Marc Piechaczyk 1,2,* and Guillaume Bossis 1,2,* 1 Institut de Génétique Moléculaire de Montpellier (IGMM), University of Montpellier, CNRS, Montpellier, France; [email protected] (M.B.); [email protected] (M.C.); [email protected] (D.T.) 2 Equipe Labellisée Ligue Contre le Cancer, Paris, France * Correspondence: [email protected] (M.P.); [email protected] (G.B.) Abstract: One major role of the eukaryotic peptidic post-translational modifier SUMO in the cell is transcriptional control. This occurs via modification of virtually all classes of transcriptional actors, which include transcription factors, transcriptional coregulators, diverse chromatin components, as well as Pol I-, Pol II- and Pol III transcriptional machineries and their regulators. For many years, the role of SUMOylation has essentially been studied on individual proteins, or small groups of proteins, principally dealing with Pol II-mediated transcription. This provided only a fragmentary view of how SUMOylation controls transcription. The recent advent of large-scale proteomic, modifomic and genomic studies has however considerably refined our perception of the part played by SUMO in gene expression control. We review here these developments and the new concepts they are at the origin of, together with the limitations of our knowledge. How they illuminate the SUMO-dependent Citation: Boulanger, M.; transcriptional mechanisms that have been characterized thus far and how they impact our view of Chakraborty, M.; Tempé, D.; SUMO-dependent chromatin organization are also considered.
    [Show full text]
  • Sexual Dimorphism in Diverse Metazoans Is Regulated by a Novel Class of Intertwined Zinc Fingers
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Sexual dimorphism in diverse metazoans is regulated by a novel class of intertwined zinc fingers Lingyang Zhu,1,4 Jill Wilken,2 Nelson B. Phillips,3 Umadevi Narendra,3 Ging Chan,1 Stephen M. Stratton,2 Stephen B. Kent,2 and Michael A. Weiss1,3–5 1Center for Molecular Oncology, Departments of Biochemistry & Molecular Biology and Chemistry, The University of Chicago, Chicago, Illinois 60637-5419 USA; 2Gryphon Sciences, South San Francisco, California 94080 USA; 3Department of Biochemistry, Case Western Reserve School of Medicine, Cleveland, Ohio 44106-4935 USA Sex determination is regulated by diverse pathways. Although upstream signals vary, a cysteine-rich DNA-binding domain (the DM motif) is conserved within downstream transcription factors of Drosophila melanogaster (Doublesex) and Caenorhabditis elegans (MAB-3). Vertebrate DM genes have likewise been identified and, remarkably, are associated with human sex reversal (46, XY gonadal dysgenesis). Here we demonstrate that the structure of the Doublesex domain contains a novel zinc module and disordered tail. The module consists of intertwined CCHC and HCCC Zn2+-binding sites; the tail functions as a nascent recognition ␣-helix. Mutations in either Zn2+-binding site or tail can lead to an intersex phenotype. The motif binds in the DNA minor groove without sharp DNA bending. These molecular features, unusual among zinc fingers and zinc modules, underlie the organization of a Drosophila enhancer that integrates sex- and tissue-specific signals. The structure provides a foundation for analysis of DM mutations affecting sexual dimorphism and courtship behavior.
    [Show full text]
  • UNIVERSITY of CALIFORNIA, SAN DIEGO the Role of Nonsense
    UNIVERSITY OF CALIFORNIA, SAN DIEGO The Role of Nonsense-mediated RNA Decay in Arsenic Toxicity A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Neurosciences by Alexandra E. Goetz Committee in Charge: Professor Miles Wilkinson, Chair Professor Nicola Allen Professor Jonathan Lin Professor Jens Lykke-Andersen Professor Pamela Mellon 2018 Signature Page The Dissertation of Alexandra E. Goetz is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2018 iii DEDICATION Dedication This work would not have been possible without the support of my family members- my mother, my father, and my brother Matt. Their support to follow my passions, even when the going got tough, helped me finish graduate school, lab change and all. I also want to dedicate this to my husband, Nadav, who was the best shoulder to cry on, cheerleader, and partner to celebrate with through graduate school. iv TABLE OF CONTENTS Table of Contents Signature Page .......................................................................................................................... iii Dedication .................................................................................................................................. iv Table of Contents ........................................................................................................................ v List of Abbreviations ................................................................................................................
    [Show full text]
  • Role of Gcn4p in Nutrient-Controlled Gene Expression in Saccharomyces Cerevisiae
    Role of Gcn4p in nutrient-controlled gene expression in Saccharomyces cerevisiae Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität vorgelegt von Olav Grundmann aus Göttingen Göttingen 2001 D7 Referent: Prof. Dr. G. H. Braus Korreferent: Prof. Dr. F. Mayer Tag der mündlichen Prüfung: 27.Juni.2001 Table of Contents I Table of Contents Summary................................................................................................................ 1 Zusammenfassung.............................................................................................. 3 Chapter I: Introduction.......................................................................................................... 5 Regulation of morphology of the bakers’ yeast Saccharomyces cerevisiae in dependence on the nutritional conditions.............................................................. 5 Life cycle of Saccharomyces cerevisiae.............................................................. 5 Pseudohyphal growth of Saccharomyces cerevisiae......................................... 6 Environmental stimuli and sensing systems..................................................... 7 Signaling pathways............................................................................................. 8 FLO11 is indispensable for filamentous growth.............................................. 11 Why studying pseudohyphal development in Saccharomyces cerevisiae?.... 12 Regulation of amino acid biosynthesis
    [Show full text]
  • The LRF Transcription Factor Regulates Mature B Cell Development and the Germinal Center Response in Mice
    The LRF transcription factor regulates mature B cell development and the germinal center response in mice Nagisa Sakurai, … , Ravi Bhatia, Takahiro Maeda J Clin Invest. 2011;121(7):2583-2598. https://doi.org/10.1172/JCI45682. Research Article Immunology B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cell–specific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies. Find the latest version: https://jci.me/45682/pdf Research article The LRF transcription factor regulates mature B cell development and the germinal center response in mice Nagisa Sakurai,1 Manami Maeda,1 Sung-Uk Lee,1 Yuichi Ishikawa,1 Min Li,2 John C. Williams,3 Lisheng Wang,1 Leila Su,3 Mai Suzuki,1 Toshiki I. Saito,4 Shigeru Chiba,5 Stefano Casola,6 Hideo Yagita,7 Julie Teruya-Feldstein,8 Shinobu Tsuzuki,9 Ravi Bhatia,1 and Takahiro Maeda1 1Division of Hematopoietic Stem Cell and Leukemia Research, 2Department of Information Sciences, and 3Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA.
    [Show full text]
  • Cooperative Dimerization of Paired Class Homeo Domains on DNA
    Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Cooperative dimerization of Paired class homeo domains on DNA David Wilson, Guojun Sheng, Thomas Lecuit, Nathalie Dostatni, and Claude Desplan Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021-6399 USA Homeo domain-containing proteins mediate many transcriptional processes in eukaryotes. Because nearly all animal homeo proteins are believed to bind to short, highly related DNA sequences, the basis for their high specificity of action is not understood. We show that cooperative dimerization on palindromic DNA sequences can provide increased specificity to one of the three major classes of homeo domains, the Paired/Pax class. The 60-amino-acid homeo domains from this class contain sufficient information to bind cooperatively as homo- and heterodimers to palindromic DNA sequences; that is, the binding of one homeo domain molecule can increase the affinity of a second molecule by up to 300-fold. Different members of the Paired (Prd) class of homeo domains prefer different spacings between half-sites, as determined by the ninth amino acid residue of the recognition helix. In addition, this residue determines the identity of the base pairs at the center of the palindromic sites, as well as the magnitude of the cooperative interaction. The cooperative dimerization of homeo domains in the Prd class distinguishes them from other classes, whereas binding-site configuration and sequence specificity allow for distinctions within this class. [Key Words: Cooperativity; dimerization; DNA binding; homeo domain; recognition helix; transcription] Received July 9, 1993; revised version accepted August 26, 1993.
    [Show full text]
  • Mutations in the Glucocorticoid Receptor Zinc Finger Region That Distinguish Interdigitated DNA Binding and Transcriptional Enhancement Activities
    Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Mutations in the glucocorticoid receptor zinc finger region that distinguish interdigitated DNA binding and transcriptional enhancement activities Mark Schena^ Leonard P. Freedman, and Keith R. Yamamoto Department of Biochemistry and Biophysics, University at Cahfomia-San Francisco, San Francisco, California 94143-0448 USA Mammalian glucocorticoid receptors bind specifically to glucocorticoid response element (GRE) DNA sequences and enhance transcription from GRE-linked promoters in mammalian cells and in yeast. We randomly mutagenized a segment of the receptor encompassing sequences responsible for DNA-binding and transcriptional regulation and screened in yeast for receptor defects. The mutations all mapped to a 66-amino- acid subregion that includes two zinc fingers; in general parallel phenotypes were observed in yeast and animal cells. Mutants defective for DNA binding also failed either to enhance or to repress transcription. However, several mutations in the second finger selectively impaired enhancement; we suggest that such 'positive control' mutants may alter protein-protein contacts required for transcriptional activation. [Key Words: GRE; zinc finger domain; DNA binding; transcription] Received July 5, 1989; revised version accepted August 14, 1989. In the presence of bound hormone, the glucocorticoid trahedrally by four cysteine sulfur atoms, and that metal receptor protein regulates transcription initiation from coordination is essential for proper folding and DNA specific animal cell promoters used by RNA polymerase binding. In addition, a 28-amino-acid subfragment has II. The receptor enhances transcription by associating been identified, which lies downstream of the fingers, selectively with DNA sequences termed glucocorticoid that exhibits nuclear localization activity but fails to response elements (GREs) (Chandler et al.
    [Show full text]
  • Evolution of Transcription Factor Function As a Mechanism for Changing Metazoan Developmental Gene Regulatory Networks Alys M Cheatle Jarvela and Veronica F Hinman*
    Cheatle Jarvela and Hinman EvoDevo 2015, 6:3 http://www.evodevojournal.com/content/6/1/3 REVIEW Open Access Evolution of transcription factor function as a mechanism for changing metazoan developmental gene regulatory networks Alys M Cheatle Jarvela and Veronica F Hinman* Abstract The form that an animal takes during development is directed by gene regulatory networks (GRNs). Developmental GRNs interpret maternally deposited molecules and externally supplied signals to direct cell-fate decisions, which ultimately leads to the arrangements of organs and tissues in the organism. Genetically encoded modifications to these networks have generated the wide range of metazoan diversity that exists today. Most studies of GRN evolution focus on changes to cis-regulatory DNA, and it was historically theorized that changes to the transcription factors that bind to these cis-regulatory modules (CRMs) contribute to this process only rarely. A growing body of evidence suggests that changes to the coding regions of transcription factors play a much larger role in the evolution of developmental gene regulatory networks than originally imagined. Just as cis-regulatory changes make use of modular binding site composition and tissue-specific modules to avoid pleiotropy, transcription factor coding regions also predominantly evolve in ways that limit the context of functional effects. Here, we review the recent works that have led to this unexpected change in the field of Evolution and Development (Evo-Devo) and consider the implications these studies have had on our understanding of the evolution of developmental processes. Keywords: Transcription factor, Gene regulatory network, Development, Novelty Introduction have historically been considered the dominant source of Gene regulatory networks (GRNs) explain the gene GRN evolution, and this idea continues to be supported by expression states that direct a cell to establish a particular new data in the genomics era (reviewed in [2-4]).
    [Show full text]