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Proquest Dissertations Universite de Montreal Mecanisme de regulation des genes par le recepteur des oestrogenes alpha : fonction des elements de reponse des oestrogenes (ERE) en tant qu'enhancers distaux. par Julie Deschenes M.Sc. Departement de Biochimie, Institut de Recherche en Immunologic et Cancerologie Faculte de Medecine These presentee a la Faculte des etudes superieures en vue de l'obtention du grade de doctorat en Biochimie Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-45368-1 Our file Notre reference ISBN: 978-0-494-45368-1 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada Universite de Montreal Faculte des etudes superieures Cette these intitulee : Mecanisme de regulation des genes par le recepteur des oestrogenes alpha : fonction des elements de reponse des oestrogenes (ERE) en tant qu'enhancers distaux. presentee par: Julie Deschenes M.Sc. a ete evaluee par un jury compose des personnes suivantes Martine Raymond PhD, president-rapporteur Sylvie Mader PhD, directeur de recherche Alain Verreault PhD, membre du jury Josee Dostie PhD, examinateur externe Ill Resume Ayant de nombreuses cibles tissulaires, les oestrogenes jouent des roles diversifies chez l'humain. Leur principal role au niveau cellulaire est la regulation de la proliferation. Les recepteurs des oestrogenes (ER) appartiennent a la grande famille des recepteurs nucleaires steroi'diens, et agissent par liaison directe a l'ADN. lis reconnaissent un element de reponse palindromique de 15 pb (ERE). Les donnees cristallographiques indiquent que la liaison a l'ADN ne se fait pas exactement comme celles des autres recepteurs nucleaires. L'etude exhaustive des acides amines responsables de la liaison aux deux nucleotides centraux de l'ERE a demontre qu'il est possible de changer la specificite de liaison du recepteur en remplacant ces acides amines. Bien que cette specificite et la selectivite du ER envers l'ADN soient connues et que plusieurs genes cibles des oestrogenes soient identifies, peu de ERE de haute affinite sont repertories. La recherche de ces ERE dans le genome de la souris et de l'humain a etabli qu'ils sont distribues dans l'ensemble du genome, avec un enrichissement dans la region proximale de 1'initiation de la transcription des genes. Le nombre eleve de ces ERE souleve la question de la fonctionnalite in vivo de ces elements. Des genes cibles primaires des oestrogenes ont ete identifies dans une lignee de cellules derivee d'un carcinome mammaire en presence d'un inhibiteur de la synthese proteique. Un fort enrichissement des ERE predits se retrouve a proximite des genes primaires positivement regules par les oestrogenes. L'etude du promoteur du gene GREB1, fortement exprime dans les tumeurs mammaires et semblant jouer un role dans la proliferation cellulaire, a demontre que les trois ERE consensus situes dans le promoteur peuvent collaborer entre eux pour medier la transcription du gene, malgre une grande distance (20 K pb) les separant. Des etudes de boucles de chromatine ont permis de developper un modele de cooperation entre les ERE afin de participer a la transcription de ce gene en presence d'oestrogenes. L'ensemble de ces etudes permet de comprendre a la fois les mecanimes de liaison du ER sur l'ADN et demontre que la regulation des genes par les oestrogenes peut se faire via des elements lointains. Mots-cies: cestrogene, r6cepteur nucleaire, ERa, ERE, gene, transcription, MCF7, GREB1, boucle de chromatine. IV Abstract Estrogens play pleiotropic roles in their different target tissues in the human body. At the cellular level, one of their major effects is to induce cellular proliferation. The estrogen receptors (ERs) are members of the steroid nuclear receptor family. Once bound to estrogens, they effect their action through direct binding to a specific 15bp palindromic DNA sequences (EREs). The crystallographic data ER-ERE complexes demonstrated intricate interactions in the central base pairs of the ERE. Our study of two amino acids important for this binding demonstrated that it is possible to alter the ER DNA binding in the specificity changing the identity of these amino acids. However, although the selectivity of the receptors for DNA is now well characterized and several target genes are identified, only a few EREs have been characterized previously. Our screening for high-affinity EREs in the entire mouse and human genome demonstrated a distribution of EREs throughout the genome, with an enrichment in the vicinity of the transcriptional start sites of genes. The high-frequency of EREs in the genome raised the question of their functional role in vivo. Estrogen primary target genes in breast carcinoma cell lines were identified by expression microarrays in presence of a protein synthesis inhibitor. An enrichment in EREs was found in the vicinity of estrogen primary up-regulated genes. Finally, we studied the promoter of the primary target gene GREB1, a gene expressed in breast tumors and involved in cell proliferation. We demonstrated that its three consensus EREs, spread over 20 Kbp of promoter region, cooperate for the transcriptional regulation of GREB1 by estrogen. Chromatin loop studies suggested a multi-partite model of enhancer for its transcription. All these studies increased the understanding of the mechanisms involved in ER DNA binding and demonstrated long-range regulation of transcription by ERs. Keywords : estrogen, nuclear receptor, ERa, ERE, gene, transcription, MCF7, GREB1, chromatin loop. Table des matieres RESUME III ABSTRACT IV TABLE DES MATIERES V LISTE DES TABLEAUX VIII LISTE DES FIGURES IX LISTE DES SIGLES ET ABREVIATIONS XII REMERCIEMENTS XV PREMIERE PARTIE 1 CHAPITRE 1 : LES OESTROGENES : HORMONES STEROIDIENNES 2 1.1 SYNTHESE ET DEGRADATION 2 l .2 ROLES ET FONCTIONS PHYSIOLOGIQUES 5 1.2.1 Le tractus reproducteur 5 1.2.1.1 Chez l'homme 5 1.2.1.2 Chez la femme 7 1.2.2 Les glandes mammaires 9 1.2.3 Les tissus osseux 10 1.2.4 Le systeme nerveux 11 1.2.5 Le systeme cardiovasculaire 12 1.3 LES MALADIES ASSOCIEES AUX OESTROGENES 12 CHAPITRE 2 : RECEPTEURDES OESTROGENES, MEDIATEURDE LA SIGNALISATION CELLULAIRE 15 2.1 LES RECEPTEURS NUCLEAIRES DES OESTROGENES 16 2.1.1 Dualite de fonction : recepteur et facteur de transcription 16 2.1.2 L'activation et les modifications post-transcriptionelles 19 VI 2.1.3 La liaison a l'ADN 21 2.1.4 La distribution tissulaire 23 2.1.5 Les recepteurs orphelins relies aux oestrogenes (ERR) 24 2.2 LA SIGNALISATION DES (ESTROGENES 25 2.2.1 Signalisation nucleaire classique 26 2.2.1.1 Les cofacteurs de la signalisation nucleaire 26 2.2.1.2 Recrutement ordonne des complexes impliques dans la signalisation classique 27 2.2.2 Signalisation nucleaire alternative 29 2.2.3 Signalisation membranaire : mode d'action rapide des oestrogenes 30 CHAPITRE 3 : CHROMATINE ET TRANSCRIPTION DES GENES 33 3.1 L'ORGANISATION SPATIO-TEMPORELLE DE LA CHROMATINE 33 3.1.1 Les composantes des promoteurs 34 3.1.2 Structure tridimensionnelle et dynamique de la chromatine 36 3.2 REGULATION DE LA TRANSCRIPTION A LONGUE DISTANCE 40 3.2.1 La mise a jour du concept de promoteur 41 3.2.2 Les boucles de chromatines 43 CHAPITRE 4 : PROBLEMATIQUES 47 DEUXIEME PARTIE 49 CHAPITRE 5 : GENOME-WIDE IDENTIFICATION OF HIGH AFFINITY ESTROGEN RESPONSE ELEMENTS IN HUMAN AND MOUSE 50 CHAPITRE 6 : MECHANISMES OF GENE REGULATION BY ESTROGEN RECEPTOR ALPHA IN BREAST CANCER CELLS. 106 CHAPITRE 7 : REGULATION OF GREB1 TRANSCRIPTION BY ESTROGEN RECEPTOR ALPHA THROUGH A MULTIPARTITE ENHANCER SPREAD OVER 20 KB OF UPSTREAM FLANKING SEQUENCES 157 Vll TROISIEME PARTIE 180 CHAPITRE 8 : DISCUSSION ET PERSPECTIVES 181 8.1 FIXATION A L'ADN DE ER A L'ECHELLE DU GENOME 182 8.1.1 La prediction de site de fixation de ER in silico 183 8.1.2 Les sites de liaison predits sont-ils lies in vivo? 185 8 .2 GENES DIRECTEMENT REGULES PAR ERA 186 8.2.1 ERa mediateur de la signalisation oestrogenique pour tous les genes regules? 187 8.2.2 Les roles fonctionnels des genes regules directement par ER 188 8.3 MECANISTIQUE DE LA TRANSCRIPTION SUR DE LONGUES DISTANCES 190 8.3.1 Les ERE distaux sont impliques dans la formation de boucle de chromatine.
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