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Circadian Modulation of Genome-Wide Rxr Binding in Mouse Liver Tissue

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Circadian Modulation of Genome-Wide Rxr Binding in Mouse Liver Tissue Unicentre CH-1015 Lausanne http://serval.unil.ch Year : 2019 CIRCADIAN MODULATION OF GENOME-WIDE RXR BINDING IN MOUSE LIVER TISSUE Trang Khanh Bao Trang Khanh Bao, 2019, CIRCADIAN MODULATION OF GENOME-WIDE RXR BINDING IN MOUSE LIVER TISSUE Originally published at : Thesis, University of Lausanne Posted at the University of Lausanne Open Archive http://serval.unil.ch Document URN : urn:nbn:ch:serval-BIB_C4CE7516215F0 Droits d’auteur L'Université de Lausanne attire expressément l'attention des utilisateurs sur le fait que tous les documents publiés dans l'Archive SERVAL sont protégés par le droit d'auteur, conformément à la loi fédérale sur le droit d'auteur et les droits voisins (LDA). A ce titre, il est indispensable d'obtenir le consentement préalable de l'auteur et/ou de l’éditeur avant toute utilisation d'une oeuvre ou d'une partie d'une oeuvre ne relevant pas d'une utilisation à des fins personnelles au sens de la LDA (art. 19, al. 1 lettre a). A défaut, tout contrevenant s'expose aux sanctions prévues par cette loi. Nous déclinons toute responsabilité en la matière. Copyright The University of Lausanne expressly draws the attention of users to the fact that all documents published in the SERVAL Archive are protected by copyright in accordance with federal law on copyright and similar rights (LDA). Accordingly it is indispensable to obtain prior consent from the author and/or publisher before any use of a work or part of a work for purposes other than personal use within the meaning of LDA (art. 19, para. 1 letter a). Failure to do so will expose offenders to the sanctions laid down by this law. We accept no liability in this respect. Département of Genomics CIG - Centre Intégratif de Génomique CIRCADIAN MODULATION OF GENOME-WIDE RXR BINDING IN MOUSE LIVER TISSUE Thèse de doctorat ès sciences de la vie (PhD) programme Integrative Experimental and Computational Biology présentée à la Faculté de biologie et de médecine de l’Université de Lausanne par Khanh Bao TRANG M.D diplômé, l’Université de Pharmacie et Médicine d’Ho-Chi-Minh-Ville, Vietnam Maîtrise en Santé Publique, Université de Debrecen, Hongrie Jury Prof. Nicolas SALAMIN, Président Prof. Béatrice DESVERGNE, Directeur de thèse Dr Nicolas GUEX, Co-directeur de thèse Dre Mercedes RICOTE, expert Dr Philipp BUCHER, expert Prof. Ioannis Xenarios, expert Lausanne 2019 UNIL I Université de Lausanne Ecole Doctorale Faculté de biologie boctorat ès sciences de la vie et de médecine Imprimatur Vu le rapport présenté par le jury d'examen, composé de Président.e Monsieur Prof Nicolas Salamin Directeur.trice de thèse Madame Prof Béatrice Desvergne Co-directeur.trice Monsieur Dr Nicolas Guex Xenarios Expert.e.s Monsieur Prof Ioannis Madame Dre Mercedes Ricote Monsieur Dr Philipp Bucher le Conseil de Faculté autorise I'impression de la thèse de Madame Khanh Bao Trang Master of Public Health, University of Debrecen, Hongrie intitulée Circadian modulation of genome-wide RXR binding in mouse Iiver tissue Lausanne, le ll juillet 20L9 pour le Do de la Faculté et médecine Prof. las Salamin ACKNOWLEDGEMENT For Nicolas – “the wind”, who lifted my bioinformatic passion, and for Beatrice – “the string”, who kept my head earth-bound and steady. You flew my kite high and strong. Khanh – “the kite” TABLE OF CONTENT SUMMARY .................................................................................................................................................................................... 1 RÉSUMÉ ........................................................................................................................................................................................ 2 ABBREVIATIONS ....................................................................................................................................................................... 3 1. INTRODUCTION .............................................................................................................................................................. 5 1.1 RXR AS THE CENTRAL MEMBER OF NUCLEAR RECEPTORS SUPERFAMILY .............................................................................. 6 1.1.1 The discovery of Nuclear receptor and the birth of the Molecular Endocrinology field ............................ 6 1.1.2 Nuclear receptors genes and their evolution ................................................................................................................ 9 1.1.3 The modular structure of RXR, and more broadly of all the NRs ....................................................................... 13 1.1.3.1 The A/B domain .......................................................................................................................................................................... 13 1.1.3.2 The C domain ................................................................................................................................................................................ 15 1.1.3.3 The D domain ............................................................................................................................................................................... 15 1.1.3.4 The E domain ................................................................................................................................................................................ 16 1.1.3.5 The F domain ................................................................................................................................................................................ 18 1.1.4 The dimerization property of NR and the specific role of RXR in heterodimerization ............................. 19 1.1.5 The controversial existence of endogenous ligands for RXR ................................................................................ 25 1.1.6 RXR specific biological functions ...................................................................................................................................... 30 1.1.6.1 Total ablation and the roles of RXR isotypes in embryogenesis ............................................................................ 30 1.1.6.2 Tissue specific ablation and diverse effects .................................................................................................................... 34 1.1.6.3 Clinical relevance of subtypes ............................................................................................................................................... 35 1.2 THE INVOLVEMENT OF RXR IN CIRCADIAN RHYTHM ............................................................................................................. 36 1.2.1 The CycliX project: interrogating the coordination of circadian, nutrient and cell cycles by transcription factors, including NRs ................................................................................................................................................. 36 1.2.1.1 The global landscape of epigenetics along the diurnal cycle ................................................................................... 38 1.2.1.2 The integrating circadian cycle with feeding rhythm ................................................................................................. 39 1.2.1.3 Cell cycle - the third cog coming into focus ..................................................................................................................... 40 1.2.2 The possible role of RXR in coordinating the three liver cycles .......................................................................... 40 1.2.3 Aim of the project .................................................................................................................................................................... 43 2. EXPERIMENTAL MATERIALS AND METHODS .................................................................................................... 44 2.1 ANIMALS AND TREATMENT ........................................................................................................................................................ 45 2.2 CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY SEQUENCING PROTOCOL (CHIP-SEQ) .......................................... 46 2.3 CHIP-SEQ LIBRARY CONTROL AND READ MAPPING ................................................................................................................ 47 2.4 PEAK CALLING ............................................................................................................................................................................... 49 2.4.1 Identifying the enriched regions ....................................................................................................................................... 49 2.4.2 Peak refinement within the regions ................................................................................................................................ 51 2.5 MOTIF ANALYSIS ........................................................................................................................................................................... 54 2.6 GENES ENRICHMENT ANALYSIS .................................................................................................................................................. 54 2.7 BIOINFORMATICS TOOLS ............................................................................................................................................................. 55 2.8 LIST OF USED DATA SETS
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