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Dérégulations Épigénétiques Induites Par La Protéine Fusion BRD4-NUT Et

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Dérégulations Épigénétiques Induites Par La Protéine Fusion BRD4-NUT Et Dérégulations épigénétiques induites par la protéine fusion BRD4-NUT et caractérisation de la proteine NUT au cours de la spermatogenèse et dans les cancers Nicolas Reynoird To cite this version: Nicolas Reynoird. Dérégulations épigénétiques induites par la protéine fusion BRD4-NUT et caractéri- sation de la proteine NUT au cours de la spermatogenèse et dans les cancers. Biochimie [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2010. Français. tel-00534655 HAL Id: tel-00534655 https://tel.archives-ouvertes.fr/tel-00534655 Submitted on 10 Nov 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE DE GRENOBLE Spécialité Biologie Cellulaire Arrêté ministériel : 7 août 2006 Présentée et soutenue publiquement par NICOLAS REYNOIRD Le 2 Novembre 2010 DEREGULATIONS EPIGENETIQUES INDUITES PAR LA PROTEINE FUSION BRD4-NUT, ET CARACTERISATION DE LA PROTEINE NUT AU COURS DE LA SPERMATOGENESE ET DANS LES CANCERS Thèse dirigée par Dr. Saadi KHOCHBIN COMPOSITION DU JURY : Stefan NONCHEV Professeur à Grenoble Président du jury Didier TROUCHE Docteur à Toulouse Rapporteur Pierre-Antoine DEFOSSEZ Docteur à Paris Rapporteur Zdenko HERCEG Docteur à Lyon Examinateur Saadi KHOCHBIN Docteur à Grenoble Examinateur Thèse préparée au sein du laboratoire CRI Inserm/UJF U823, Institut Albert Bonniot, dans l’Ecole Doctorale Chimie et Sciences du Vivant A ma famille, A muriel. p. 1 Remerciements Je tiens à remercier particulièrement l’ensemble des membres de mon jury de thèse, qui ont si gentiment accepté d’évaluer mes quatre années de travaux de doctorat. Merci donc aux Docteurs Pierre-Antoine Defossez et Didier Trouche pour leur regard critique de rapporteurs sur ces travaux. Je remercie également le Docteur Zdenko Herceg et le professeur Stefan Nonchev pour avoir accepté de juger mon doctorat et de participer à sa soutenance. Je remercie bien évidemment le Docteur Saadi Khochbin pour m’avoir accueilli au sein de son laboratoire. Ce fut un grand honneur de pouvoir travailler sous sa direction et apprendre la Science et le monde de la recherche à travers son expérience. Sa disponibilité et sa gentillesse à chaque instant m’ont permis de me rendre compte de la chance que j’ai eu de pouvoir travailler dans des conditions optimales de travail. Des discussions critiques, une diplomatie à toute épreuve et la liberté de travail sont la meilleure des formations. Merci Saadi. Je remercie également la région Rhône-Alpes et la Fondation pour la Recherche Médicale pour leur soutien financier et la confiance qu’ils ont accordée à mes travaux. Le nerf de la guerre, même en Science. Je tiens à remercier les membres de l’équipe et de l’Institut qui n’ont pas rechigné à prendre de leur temps pour discuter et partager leurs expériences. Merci donc à Sophie, Karine, Cécile, Claire, André, Faycal et Olivier, entre beaucoup d’autres. Merci aux personnes de l’Institut qui ont participé de près ou de loin à ce projet de thèse, ou qui m’ont tout simplement rendu service à un moment donné. Merci donc notamment à Sandrine pour sa gestion exemplaire des petites choses qui font survivre le labo, et à Aude pour sa patience envers mon ignorance rare face aux problèmes administratifs. Il est impossible d’avancer seul, en Recherche comme ailleurs. Un grand merci donc à toutes les personnes qui m’ont aidé au cours de cette période de ma vie. Vous rencontrer m’a permis de forger mon expérience et surpasser les petits tracas du quotidien, en plus d’agrandir p. 2 mon cercle d’amis. Merci donc aux « anciens » qui ont forgé mes débuts: Cyril (Savoie, main sur le coeur), Rico (geek et « in » à la fois), Charrette (et son chinois), Yannick (le frontalier), NJ (et ses mollets), Jérome (le doubiste),… Keep in touch guys. Merci à la nouvelle génération, plus forte que les beatniks, qui a su consolider les bases: Seb (the Dude), Johny (et son double), Faycal (Clooney), Sophie (CSBJ 4ever), Sevgi (saveyouroom), Aurelia (la censure), Leila (c’est bon les baklavas !), Edwige (et ses syncopes), Emeline (mortal kombat), Gaetan (ah, la saucisse de Toulouse…), Emilie (j’ai trouvé plus bordélique), the Aurore show, Néda (et toutes ses questions) et j’en oublie forcément. Les longues heures de boulot passent toujours plus vite en bonne compagnie. Merci aux potos qui m’ont permis de sortir la tête de la science quand il le fallait, et de voir plus loin que le bout de mes cellules, que ce soit autour d’une bière ou en haut d’une montagne. San Francisco vous attend, n’hésitez pas. Une petite pensée au chat de mes propriétaires, de par son support infaillible, à venir squatter mes genoux lors de l’écriture de ce manuscrit. Merci à ma famille, pour le soutien permanant et tout ce que vous m’avez apporté jusque la. Je mesure chaque jour la chance que j’ai de pouvoir compter sur vous quoi qu’il advienne. Vous vous en doutez, c’est réciproque. Merci également à la belle-famille, pour son soutien et son aide pour la relecture indigeste de ce manuscrit. Enfin, on garde toujours le meilleur pour la fin, comme on dit. Merci donc à toi Mu, pour ton amour, ta joie de vivre et celle que tu me procures. Tes passions, ton insatiable appétit d’aventure et ta force de caractère m’ont permis de découvrir de si belles choses, autant que de me découvrir moi-même. Tu m’as permis de m’investir dans mon travail et ton support m’a réconforté lorsque les résultats tardaient à venir. Merci pour ta patience et tes efforts après mes « trop » longues journées de travail, et plus que tout, merci de prolonger l’aventure à mes cotés jusqu’en Californie. Miaouh… p. 3 Sommaire p. 4 Sommaire .................................................................................................................................... 4 Résumé ...................................................................................................................................... 10 Abstract ..................................................................................................................................... 11 Abrévations................................................................................................................................ 12 Liste des Figures ......................................................................................................................... 13 Introduction ............................................................................................................................... 14 I) Structure, dynamique et plasticité de la chromatine .................................................................... 15 IA) Définition et structure de la chromatine ............................................................................................... 15 IA1) Définition ......................................................................................................................................... 15 IA2) Le nucléosome, unité de base de la chromatine ............................................................................. 17 IA3) Les autres niveaux de structuration de la chromatine .................................................................... 21 IB) Dynamique et plasticité de la chromatine ............................................................................................. 24 IB1) Organisation structurelle de la chromatine ..................................................................................... 24 IB2) Organisation spatiale de la chromatine ........................................................................................... 25 II) L’information épigénétique et ses acteurs ................................................................................... 27 IIA) Présentation de l’épigénome ................................................................................................................ 27 IIB) Les différentes informations épigénétiques et leurs acteurs ................................................................ 30 IIB1) La méthylation de l’ADN ................................................................................................................. 30 IIB2) Les ARN non codants ...................................................................................................................... 36 IIB3) Les modifications des histones ....................................................................................................... 38 IIB3a) Introduction ............................................................................................................................. 38 IIB3b) Phosphorylation ....................................................................................................................... 41 IIB3c) Méthylation .............................................................................................................................. 42 IIB3ci) Les histones méthyltransférases ........................................................................................ 42 IIB3cii) Les histones déméthylases ...............................................................................................
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