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UNIVUNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALRALE « des Sciences de la vie et de la santé » IGBMCC – Inserm U 964 – CNRS UMR 7104104 THÈSE présentée par : Lise-Marie DONNIO Soutenue le : 15 décembre 2014 Pour obtenirir le grade de : Docteur de l’université de Strasbrasbourg Discipline/Spécialité : Scienceences du Vivant/Aspects Moléculaires et Cellulallulaires de la Biologie Étudee tratranscriptionnelle des mutationtions dans le Médiaédiateur ou dans son partenaireaire NIPBL à l’orig’origine de maladies génétiques Thèse dirigée par : Dr EGLY Jean-Marc DRE INSERM,M, IIGBMC, Strasbourg RAPPORTEURS : Dr JALINOT Pierre DR CNRS, ENS Lyon Dr BROUSSET Pierre PR INSERM,, CHCHU Toulouse Pr DOLLFUS Hélène PR INSERM,, CHCHRU Strasbourg ACKNOWLEDGEMENTS Je tiens tout d’abord à exprimer mes remerciements à Pierre JALINOT, Pierre BROUSSET et Hélène DOLLFUS de m’avoir fait l’honneur d’accepter d’être membres de mon jury et ainsi participer à la dernière étape de ma thèse. Je remercie tout particulièrement Jean-Marc EGLY, pour m’avoir accueilli dans son laboratoire situé dans l’un des meilleurs centres scientifiques internationaux et pour avoir été mon directeur de thèse. Merci pour sa confiance tout au long de ces quatre années. Merci à l’Association de la Recherche contre le Cancer et à la Ligue contre le cancer, ainsi que leurs nombreux donateurs pour avoir financés les deux dernières années de mes études doctorales. Merci à tous les membres du laboratoire présents et passés (Annabel, Anton, Amita, Alex, Alexey, Baptiste, Cathy, Carlos, Charlotte, Christophe, Federico, Frédéric, Hussein, Izarn, Jikta, Manu, Maryssa, Marc, Nicolas, Philippe, Renier, Salim, Satoru, Serena, Sergey, Ulrik, Valérie, Yakov, Zita). Je remercie particulièrement Baptiste, mon compagnon de galère sur le projet Médiateur, pour les discussions scientifiques et bavardages en tous genres, ainsi que Manu pour toutes ses corrections. Un merci général pour l’ambiance (au labo et en dehors), ainsi que pour les nombreuses et vraiment très diverses discussions que nous avons eues. Je tiens à clamer haut et fort que le box 4025 est le plus cool. Je remercie tous les membres des services communs de l’IGBMC et en particulier les membres du service de culture cellulaire. Je remercie l’ensemble de mes amis (Julia, Christelle, Nico, Yvan, Céline, Elodie, Cyril, William, Laurence, Julien…etc) pour les nombreuses discussions sans rapport avec la recherche et les très nombreuses soirées jeux. Du côté musical, je n’oublie pas les membres des Sixtoys et de l’orchestre Vulcania, qui m’ont permis le temps d’une répétition ou d’un concert, d’oublier le quotidien du labo. Finalement, et il va sans dire, je remercie de tout mon cœur ma famille (papa, maman, mes sœurs, mon petit frère, mes neveux et nièces) sans qui rien de tout cela n’aurait été possible, même si le sujet de ma thèse restera en partie un mystère pour eux. En espérant n’avoir oublié personne… merci à tous ! 1 CONTENTS FIGURES AND TABLES ............................................................................................. 4 ABBREVIATIONS ...................................................................................................... 5 RÉSUMÉ DE LA THÈSE EN FRANÇAIS ..................................................................... 7 INTRODUCTION .................................................................................... 14 I. Transcription of class II genes .................................................................................................... 15 A. RNA polymerase II .......................................................................................................................... 15 A.1. Subunit composition .................................................................................................................................................... 15 A.2. Structure of Pol II .......................................................................................................................................................... 16 A.3. CTD and its modifications ......................................................................................................................................... 17 B. Regulatory sequence in the heart of DNA ...................................................................................... 17 B.1. The core promoter ........................................................................................................................................................ 17 B.1.a. The TATA-box ..................................................................................................................................................... 18 B.1.b. The initiator element (Inr) ............................................................................................................................ 18 B.1.c. The TFIIB recognition element (BREu and BREd) ............................................................................... 18 B.1.d. The Downstream promoter element (DPE) ............................................................................................ 18 B.1.e. The Motif ten element (MTE) ....................................................................................................................... 19 B.1.f. The downstream core element (DCE) ........................................................................................................ 19 B.1.g. The X core promoter element 1 (XCPE1) ................................................................................................. 19 B.2. Regulatory response element .................................................................................................................................. 19 C. General transcription factors.......................................................................................................... 20 D. The transcription cycle ................................................................................................................... 22 D.1. Promoter binding .......................................................................................................................................................... 22 D.2. Initiation and promoter clearance ........................................................................................................................ 22 D.3. Proximal pausing and elongation .......................................................................................................................... 24 D.4. Termination ..................................................................................................................................................................... 24 D.5. Re-initiation and gene looping ................................................................................................................................ 25 E. The activated transcription ............................................................................................................. 28 E.1. Immediate early response genes ............................................................................................................................ 28 E.2. Nuclear receptors regulated genes ........................................................................................................................ 28 E.2.a. Nuclear receptors structure.......................................................................................................................... 29 E.2.b. Nuclear receptor classification .................................................................................................................... 30 E.2.c. Retinoic acids receptors .................................................................................................................................. 30 E.2.d. Transcription of RAR target genes ............................................................................................................. 31 E.2.e. Vitamin D receptors ......................................................................................................................................... 34 II. REVIEW on the Mediator complex ........................................................................................... 35 III. Supplemental information ........................................................................................................ 64 2 Discovery of the Mediator complex ........................................................................................................................ 64 Composition and structure of the Mediator complex ..................................................................................... 64 The Mediator complex: a general transcription factor ................................................................................. 64 Cohesin complex ............................................................................................................................................................ 66 MATERIALS & METHODS ..................................................................... 69 Cells culture ..................................................................................................................................................................... 70 Isolation of mouse embryonic fibroblasts ........................................................................................................... 71 Treatments .....................................................................................................................................................................
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