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Proquest Dissertations Differential Transcriptional Modulation of Duplicated Fatty Acid-Binding Protein Genes by Dietary Fatty Acids in Zebrafish {Danio reno) by Santhosh Karanth Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia August 2010 © Copyright by Santhosh Karanth, 2010 Library and Archives Bibliothèque et ?F? Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 OttawaONK1A0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-69876-1 Our file Notre référence ISBN: 978-0-494-69876-1 NOTICE: AVIS: The author has granted a non- L'auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. 1+1 Canada DALHOUSIE UNIVERSITY To comply with the Canadian Privacy Act the National Library of Canada has requested that the following pages be removed from this copy of the thesis: Preliminary Pages Examiners Signature Page (pji) Dalhousie Library Copyright Agreement (piii) Appendices : . - Copyright Releases (if applicable) To, Mom, Tara and Vish Bhat "Life is short, craft long to learn, opportunity fleeting, experiments deceptive and judgment difficult". -Hippocrates IV Table of Contents List of Tables ix List of Figures ? Abstract xii List of Abbreviations Used xiii Acknowledgements xiv Chapter 1: Introduction 1 Nomenclature and Classification of iLBP Genes 1 Gene and Genome Duplications, and the Molecular Evolution of iLBP 2 Multigene Family in Zebrafish Structure and Functions of iLBPs 7 Spatio-Temporal Distribution of Zebrafish iLBP Transcripts in Developing „ Embryos and Larvae Tissue-Specific Distribution of iLBP Transcripts in Adult Zebrafish 10 Transcriptional Regulation of iLBP Genes 1 1 Lipid Homeostasis in Teleost Fishes 14 Objectives of This Study 16 Chapter 2: Tandem Duplication ofTh&fabplb Gene and Subsequent Divergence of the Tissue-Specific Distribution oifabplb.l andfabplb.2 Transcripts in Zebrafish 17 (Danio rerio) Abstract 18 Introduction 19 Materials and Methods 21 Husbandry of Zebrafish 2 1 Nucleotide Sequence of the Zebrafish/a¿>pi¿>. 2 cDNA and its Gene 21 Phylogenetic Analysis 22 ? Radiation Hybrid Mapping of the Zebrafishfabplb.2 Gene 22 In Situ Hybridization to Whole-Mount Embryos and Larvae, and to Sections of Adult Zebrafish 22 RT-PCR Detection offabplb.2 Transcripts in Adult Zebrafish 2_ Tissues Results and Discussion 24 Identification of a Duplicatedfabpl b Gene in the Zebrafish Genome 24 Duplicate Copies offabplb in the Zebrafish Genome may have Arisen by a Tandem Duplication Event 29 Distribution offabplb.2 Transcripts in Developing Zebrafish Embryos and Larvae 3 1 Tissue-Specific Distribution offabplb.2 Transcripts in Adult Zebrafish 34 Divergence of the Tissue-Specific Distribution offabplb. 1 and fabplb.2 Transcripts 36 Chapter 3: The Evolutionary Relationship Between the Duplicated Copies of the Zebïanshfabpl 1 Gene and the Tetrapod FABP4, FABP5, FABP8 and FABP9 39 Genes Abstract 40 Introduction 41 Materials and Methods 43 Husbandry of Zebrafish 43 Nucleotide Sequence of the Zebrafishfabpl 1 b cDNA and Its Gene 43 Phylogenetic Analysis 44 Radiation Hybrid Mapping of the Zebrafishfabpllb Gene 44 In Situ Hybridization to Whole-Mount Embryos and Larvae, and to Sections of Adult Zebrafish 44 RT-PCR Detection offabpllb Transcripts in Adult Zebrafish Tissues 45 Vl Database Searches of Genome Sequences and Identification of . , Transcription Factor Binding Sites Results and Discussion 46 Identification of a Duplicatedfabpllb Gene from Zebrafish 46 Distribution offabpllb Transcripts in the Retina of Developing Zebrafish Embryo and Larvae 49 Tissue-specific Distribution offabpllb Transcripts in Adult Zebrafish 49 Duplicate Copies offabpll in Zebrafish may have Arisen by a Fish Specific Whole-Genome Duplication Event 5 1 fabpll, FABP4, FABP5, FABP8, and FABP9 Evolved from a Common Ancestral Gene on a Single Progenitor Chromosome 58 The Tetrapod FABP5, FABP8, FABP9 and FABP4 Genes are Tandernly Arrayed and Likely Arose by Unequal Crossing-Over. f. Which Gene was Duplicated First? Chapter 4: Differential Transcriptional Modulation of Duplicated Fatty Acid- Binding Protein Genes by Dietary Fatty Acids in Zebrafish {Danio rerio): Evidence 66 for Subfunctionalization or Neofunctionalization of Duplicated Genes Abstract 67 Introduction 69 Materials and Methods 74 Diets and Fish Husbandry 74 RNA Isolation, cDNA Synthesis and RT-qPCR 78 Lipid Extraction, FAME Preparation and Gas Chromatography 80 Statistical Analysis 8 1 Results 81 The Steady-State Level oifabp mRNAs Does not Differ Between „ - Sexes of Zebrafish Effect of Diet on the FA Composition in Different Tissues of „ - Zebrafish VIl Effect of Diet on the Steady-State Level of fabpla/fabplb.l/fabplb.2 mRNAs in Different Tissues 82 Effect of Diet on the Steady-State Level of Fabp7alFabp7b mRNA in Different Tissues. 89 Effect of Diet on Steady-State Level of Fabp11 alFabpllb mRNA in Different Tissues 89 Modulation of the Steady-State Level oífabp mRNA is Due to Up- Regulation of Transcriptional Initiation 94 Discussion 97 Effect of Diet on FA Profiles in Tissues of Zebrafish 97 Dietary FAs Modulate the Steady-State Level offabp mRNAs 97 Differential Modulation oîfabplb.l, but notfabpla andfabplb.2 1 __ Transcription by Dietary FAs Tissue-Specific Transcriptional Modulation offabp7a andfabp7b mRNAs by Dietary FAs 1 02 Transcriptional Modulation offabplla, but notfabpllb, by Dietary 1 m FAs U Conclusion 103 Acknowledgements 104 Chapter 5: Conclusion 105 Role of Gene and Whole-Genome Duplications in the Evolution 1 _ _ of iLBP Multigene Family in Zebrafish Retention of Duplicatedfabp Genes in the Zebrafish Genome 106 Subfunctionalization/Neofunctionalization of Duplicatedfabp Genes in the Context of Tissue-Specific Distribution of Their Transcripts 107 Subfunctionalization/Neofunctionalization of Duplicated fabp Genes in the 109 Context of Their Transcriptional Induction by Dietary FAs Bibliography 115 Appendix A. Copyright Permission Letter from FEBS Journal 132 Appendix B. Author's Rights Policy of NRC Press 133 vni List of Tables Table 1 . 1 Zebrafish iLBP genes assigned to different linkage groups based on 5 radiation hybrid mapping (LN54 panel) Table 1.2 Transcript distribution of iLBP genes in different tissues of adult 12 zebrafish Table 2. 1 Tissue-specific distribution oífabpl transcripts in embryos and adults 37 of mammals (fabpl) and zebrafish (fabpla,fabplb.l andfabplb.2) Table 3.1 Conserved gene synteny of the duplicated copies of the zebrafish 57 fabpl 1 gene with the humanfabp4,fabp5,fabp8 andfabp9 genes Table 4. 1 Composition of experimental diets 75 Table 4.2 Major fatty acids in the experimental diets 77 Table 4.3 Primers used for the quantification offabp mRNA and hnRNA 79 Table 4.4 Fatty acid composition in intestine of zebrafish fed experimental diets 84 Table 4.5 Fatty acid composition in liver of zebrafish fed experimental diets 85 Table 4.6 Fatty acid composition in muscle of zebrafish fed experimental diets 86 Table 4.7 Fatty acid composition in brain of zebrafish fed experimental diets 87 Table 4.8 Induction of the steady-state level of mRNA and hnRNA coded by 99 fabp genes in tissues of zebrafish fed one of the four diets differing in FA content Table 5.1 Tissue-specific distribution offabpl (fabp1 a, fabplb. 1 andfabplb.2) 108 andfabpl 1 (fabpl la andfabpllb) transcripts in embryos and adults of zebrafish IX List of Figures Figure 2.1 The genomic organization of the zebvañshfabplb.2 gene 25 Figure 2.2 Phylogenetic tree of selected vertebrate Fabps showing the 27 relationship between zebrafish Fabpla, Fabplb.l and Fabplb.2. Figure 2.3 Genomic organization of the duplicatedfabplb. 1 (left) andfabplb.2 30 (right) genes on zebrafish chromosome 8 Figure 2.4 Spatio-temporal distribution offabplb.2 transcripts in embryos and 32 larvae of zebrafish and the tissue-specific distribution offabplb.2 transcripts in sections of adult zebrafish Figure 2.5 Detection offabplb. 1 andfabplb.2 transcripts
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