Méthylations De L'histone H3 Et Contrôle Épigénétique Des

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Méthylations De L'histone H3 Et Contrôle Épigénétique Des M´ethylations de l'histone H3 et contr^ole´epig´en´etique des propri´et´esdes cellules souches de gliomes Alexandra Bogeas To cite this version: Alexandra Bogeas. M´ethylations de l'histone H3 et contr^ole´epig´en´etiquedes propri´et´esdes cellules souches de gliomes. M´edecinehumaine et pathologie. Universit´eRen´eDescartes - Paris V, 2013. Fran¸cais. <NNT : 2013PA05P620>. <tel-01170633> HAL Id: tel-01170633 https://tel.archives-ouvertes.fr/tel-01170633 Submitted on 2 Jul 2015 HAL is a multi-disciplinary open access L'archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destin´eeau d´ep^otet `ala diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publi´esou non, lished or not. The documents may come from ´emanant des ´etablissements d'enseignement et de teaching and research institutions in France or recherche fran¸caisou ´etrangers,des laboratoires abroad, or from public or private research centers. publics ou priv´es. Université Paris Descartes PARIS V Ecole Doctorale MTCE «Médicament, Toxicologie, Chimie et Environnement» THÈSE de DOCTORAT de l’UNIVERSITE PARIS V Spécialité : Neurosciences En vue de l’obtention du grade de Docteur de l’Université Paris V Présentée par Alexandra BOGEAS Méthylations de l’histone H3 et contrôle épigénétique des propriétés des cellules souches de gliomes Thèse dirigée par le Dr Hervé CHNEIWEISS Soutenue le 29 Novembre 2013 Devant le Jury composé de : Madame le Docteur Sylvie ROBINE Président Monsieur le Professeur Jacques HAIESH Rapporteur Madame le Professeur Penelope KORKOLOPOULOU Rapporteur Monsieur le Docteur Ahmed IDBAIH Examinateur Madame le Docteur Isabelle PLO Examinateur Monsieur le Docteur Hervé CHNEIWEISS Directeur de thèse 1 "C'est par l'expérience que la science et l'art font leur progrès chez les hommes." Aristote A ma famille et amis, 2 Remerciements Comment conclure cette aventure de quatre ans sans remercier toutes les formidables personnes rencontrées et sans qui cette thèse n’aurait jamais pu aboutir ? Aux membres de mon jury, le Dr Sylvie ROBINE, le Pr Jacques HAIESH, le Pr Penelope KORKOLOPOULOU, le Dr Ahmed IDBAIH et le Dr Isabelle PLO, je vous remercie d’avoir fait l’honneur d’évaluer cette thèse, et en particulier aux rapporteurs, le Pr HAIESH et le Pr KORKOLOPOULOU pour vos remarques, vos conseils et corrections de ce manuscrit. A Hervé, un immense merci pour m’avoir fait confiance et m’avoir choisi pour effectuer cette thèse au sein de votre laboratoire. Vous avez toujours été à l’écoute, disponible malgré votre emploi du temps de ministre. Merci de m’avoir fait partager votre passion pour la science, et vous écouter parler de science fut toujours un immense plaisir. A Marie-Pierre, de simples mots ne suffiraient pas pour exprimer ma gratitude envers toi. Tu as toujours été là pour sortir le meilleur de moi-même. Très patiente avec moi, tu as réussi à me motiver, me donner de précieux conseils, m’encourager, m’enseigner la rigueur nécessaire, me transmettre ton dévouement envers la recherche. Je te suis infiniement redevable pour tout ce que tu m’as apporté. A Amélia, ma deuxième maman, merci pour ton aide, aussi bien morale que physique. Tu m’as toujours soutenu, écouté, étant toujours franche et n’hésitant pas à me remettre les idées en place quand c’était nécessaire ! La vie au 3 laboratoire n’aurait pas été la même sans toi. Tu sais combien tu as été et est importante pour moi. A mes collègues et amis maintenant pour la vie, Salwa, ma zouina Salwa adorée, que dire de toi à part que je te déteste ! Bon trêve de plaisanterie, tu sais bien que c’est tout le contraire, de toute façon avec toi c’est impossible que je te mente, tu lis en moi ! Depuis le jour où tu as mis les pieds dans le laboratoire, une complicité s’est tout de suite installée, qui s’est consolidée durant toutes ces années et qui ne pourra jamais être brisée. Merci pour tes conseils, l’immense aide que tu m’as apportée et les crises de rire ! A bientôt au Maroc et ailleurs ! Gustavo, meu amor, mon complice, merci à Vivaldo de t’avoir laissé venir à Paris ! Tu sais combien ta présence, ton soutien, ton amitié, ton aide a été précieuse pour moi. Merci de m’avoir fait découvrir ton pays, le Brésil, autrement que les clichés. Je n’oublierai jamais tous ces merveilleux moments passés ensemble (la bande des quatre !) et j’attends avec impatience tous les autres moments à venir ! A bientôt au Brésil et ailleurs ! Elias, que dire de toi ! Tu es le « petit » (façon de parler !) dernier de la bande à avoir débarqué au laboratoire. Mais pas le moins important au contraire ! Tu as su nous guider tous les trois, nous transmettre ton expérience. Tu as été d’une aide immense tout le long de cette thèse, surtout à la fin d’ailleurs, et cette thèse n’aurait pas été la même sans toi ! Merci de ta patience, d’avoir supporté mes « petites » crises, de ton humour parfois difficile à déceler ! Mon allié grec qui me corrige encore et encore sur mon grec ! Ξ ο α α παα γα α αα ου. Je n’oublie pas mes anciens collègues, Cécile et Silvina. Merci à Cécile de m’ avoir si bien accueillie lors de mon arrivée au laboratoire, tu as été une enseignante géniale, une amie et confidente, un soutien dans ce début de thèse sans faille et merci pour tous ces fous rire partagés. A ma petite Silvina qui a bien grandi, 4 merci infiniement pour toutes ces immuno passées ensemble, à ta patience pour toutes mes demandes ! Je n’oublierai jamais ces moments passés ensemble ! Aux autres membres du laboratoire, Jeanne-Marie, Joanna, merci infiniment pour toute votre aide et échanges qu’on a pu avoir. Vous avez toujours été là quand j’avais besoin de vous et je vous en remercie. Merci également à tout le service d’anapat’ en particulier à Aurélien. A mes collaborateurs, A l’équipe de Michèle Goodhart (Klaudia, Isabelle, Dounia, Meriem, David) à l’hôpital Saint-louis et en particulier Michèle elle-même, un immense merci pour m’avoir aussi bien acceuillie au sein de votre laboratoire. Vous avez su m’enseigner, chercher, comprendre, explorer les secrets de la technique du ChIP. A l’équipe de Christian Neri, et en particulier à François-Xavier, sans qui cette thèse n’aurait pas pu aboutir. Merci infiniment pour ton aide, ton enseignement de la bioinformatique et ta patience sans faille à mes demandes qui n’en finissaient pas ! A l’équipe de Thierry Virolle à Nice, à la plateforme MGX de Montpellier, la plateforme IGBMC de Strasbourg, la plateforme de bioinformatique de la société GenoSplice Technology. A mes amis, Aux filles, Amal, Anais, Asta, Btissam, Meriem, Najah, Thao, merci pour votre amitié, votre soutien moral, merci d’être vous, et d’avoir toujours été là dans les bons comme les mauvais moments ! Merci à Aurélie et Lisa, mes amies de toujours, vous avez toujours été à mes côtés, malgré mon absence surtout à la fin ! Je tiens également à remercier mes premiers mentors qui m’ont fait aimer et découvrir la science, Darek Gorecki, Gilles Mirambeau et en particulier Catherine Rougeot qui m’a transmis sa passion pour la science, merci de m’avoir accueillie 5 en master 2 et de m’avoir sans cesse soutenu (merci à Evelyne Dufour également !). Enfin, en dernier mais pas les moindre, merci à ma grande et belle famille. Merci à mes grands-parents, mes tantes, oncles et cousins, en France comme en Grèce, et évidemment, merci à mes parents et à mes trois sœurs sur qui j’ai toujours pu compter et qui ont été et sont d’un soutien sans faille. Sans vous je n’en serai pas là. Σα υχαω παα που γα οα, α αγαπω που. A ceux oublié, je m’en excuse mais sachez que toutes les personnes rencontrées ont été importantes pour moi. 6 Résumé Les gliomes sont les tumeurs primitives les plus fréquentes du cerveau et restent de mauvais pronostic en raison de l’inefficacité des traitements actuels. Des cellules souches cancéreuses ont été isolées à partir de gliomes de haut grade de l’adulte. Ces cellules souches de gliomes (GSC) peuvent fournir tous les sous-types cellulaires qui composent la tumeur. De nombreuses données indiquent que la résistance aux traitements est due en grande partie aux GSC. Cibler les GSC et leurs propriétés souches constitue donc un enjeu thérapeutique important. J’ai d’abord participé à déterminer la présence de GSC dans les gliomes pédiatriques. Nous avons ainsi pu isoler des GSC de gliomes pédiatriques de différents types et grades. Parvenir à cibler les GSC implique également de caractériser les voies moléculaires qui gouvernent leurs propriétés de façon spécifique afin d’épargner les cellules souches neurales normales (NSC). Dans ce cadre, j’ai participé à démontrer les effets toxiques du resvératrol sur les GSC et à déterminer les voies moléculaires qui sous-tendent la spécificité de ses effets, ce polyphénol n’agissant pas sur les NSC. Une solution pertinente de ciblage thérapeutique est de forcer les GSC à quitter leur état souche. Dans ce cadre, mes principaux travaux ont eu pour but de caractériser les changements épigénétiques des marques d’histones qui accompagnent la répression des propriétés des GSC par un groupe de micro-ARN, miR-302-367. Les GSC présentent une plasticité exceptionnelle leur permettant d’acquérir ou de perdre leurs propriétés en réponse aux signaux de leur environnement. L’étude de cette plasticité par notre équipe a abouti à l’identification de miR-302-367.
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