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Expression Génique Au Cours De La Différenciation De L'épiderme Humain

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Expression Génique Au Cours De La Différenciation De L'épiderme Humain UNIVERSITÉ TOULOUSE III - PAUL SABATIER U.F.R. Sciences de la Vie et de la Terre (SVT) École Doctorale Biologie-Santé-Biotechnologies THÈSE Pour l’obtention du grade de DOCTEUR DE L’UNIVERSITÉ TOULOUSE III Spécialité Biologie Cellulaire et Moléculaire Présentée et soutenue par Eve TOULZA le 20 octobre 2006 EXPRESSION GÉNIQUE AU COURS DE LA DIFFÉRENCIATION DE L’ÉPIDERME HUMAIN Jury : David CRIBBS Président Thierry MAGNALDO Rapporteur Philippe MUSETTE Rapporteur Daniel ABERDAM Examinateur Guy SERRE Examinateur Marina GUERRIN WEBER Directeur de thèse Unité Différenciation Épidermique et Auto-immunité Rhumatoïde UMR 5165 CNRS – Université Toulouse III, Faculté de Médecine 37, allées J. Guesde - 31073 Toulouse 1 Cette thèse, pour vous qui me lisez, c’est 282 pages, 41 illustrations, 64 762 mots, 431 168 caractères et 385 références. Mais pour moi ce fût aussi : – 152 minibanques – plus de 100 000 clones – 22 585 ORESTES – 27 000 séquences – 54 plaques de 384 puits – 1200 unités de Taq – 1 demi-milliard de cellules – 288 heures d’enseignement – 23 litres de LB – 18 flacons de trypsine – 760 microgrammes d’ARN – 550 litres de café – 468 000 marches d’escalier – 1 225 grammes d’agarose – 2,66 m² de bureau – 322 amorces de PCR quantitative – 80 gigaoctets de fichiers – 130 kilogrammes de documents – 4 ans de bons moments... 3 Remerciements J’exprime toute ma gratitude à Guy Serre pour m’avoir accueillie dans son unité. Merci de m’avoir permis de travailler dans les meilleures conditions, de m’avoir encouragée et de m’avoir fait confiance quand j’ai souhaité faire de l’enseignement. Je remercie Thierry Magnaldo, Directeur de Recherche CNRS à l’Institut Gustave Roussy (Villejuif, UPR2169 CNRS), et Philippe Musette, Professeur de dermatologie de Rouen, de me faire l’honneur d’évaluer ces travaux. Merci d’avoir accepté la lourde tâche de rapporteurs. Merci aussi à Daniel Aberdam, Directeur de Recherche INSERM (Nice, INSERM U634) et David Cribbs, Professeur de génétique à l’Université Paul Sabatier (Toulouse III) d’avoir accepté de participer au jury de cette thèse malgré un emploi du temps chargé. Mes remerciements les plus sincères à Marina Guerrin Weber, mon directeur de thèse. Sa passion pour son métier, son enthousiasme, son exigence et le soutien auquel j’ai eu droit tout au long de ces travaux, qu’il soit moral ou intellectuel, resteront mes bases et mon élan pour de futurs projets. Merci de m’avoir donné un sujet extrêmement passionnant, et de m’avoir fait confiance pendant ces 5 ans. Je voudrais également te remercier pour le temps, la disponibilité et l’énergie dont tu as fait preuve pendant cette thèse. Il me tient à coeur également d’exprimer ici toute ma reconnaissance et ma profonde amitié à Mitou Ribouchon. Mitou, tes doigts d’or, ta bonne humeur permanente et les nombreuses attentions dont tu as fait preuve à mon égard se sont révélées extrêmement précieuses depuis ton arrivée au laboratoire. Merci pour notre café du matin qui a souvent été l’occasion de plaisantes discussions. Je salue avec grand plaisir tous les membres de l’équipe et du laboratoire qui m’ont chaleureusement entourée tout au long de cette thèse. Merci en particulier à Florence Galliano pour son travail sur l’A2ML1, à Nathalie Jonca pour sa disponibilité et nos discussions enrichissantes, Hélène Gallinaro pour ses analyses immunohistochimiques. Merci à Anne Huchenq-Champagne pour avoir supporté ma pagaille avec bonne humeur. Je remercie plus particulièrement Nicolas Mattiuzzo, mon colocataire et « compagnon de transcriptome ». Merci d’avoir essayé de m’initier, en vain, au plaisir de l’analyse statistique. Merci surtout pour nos discussions concernant la biologie de l’armadillo, les chats de l’île Kerguelen ou l’alignement des orbites des planètes du système solaire sur un même plan. Merci enfin pour ta... bonhomie ! Merci également à Emilie Leclerc pour ses nombreuses relectures et ses coups de pouce salvateurs lors de la mise en forme de ce manuscrit. Merci pour ta disponibilité et pour ta bonne humeur au quotidien. Je vous souhaite à tous les deux bon courage pour vos oeuvres doctorales respectives. Céline, miss PAD6, nous avons partagé les moments d’angoisse, de doute, et parfois (?) d’espoir. Je te souhaite autant de plaisir à terminer ta rédaction que j’en ai eu à mettre un point final à ce manuscrit. Le relais qui m’a été transmis par Cécile et Rachida est désormais entre tes mains ! 5 J’ai pris beaucoup de plaisir à travailler avec les nombreux stagiaires qui ont contribué, le temps de quelques mois ou seulement de quelques séquences, à l’avancée de ces travaux : Aurélie, Christophe, Matthieu, Delphine, Emilie, Daniela, Dany, Bénédicte, Ikrame... Merci à vous. Je remercie l’équipe administrative de l’unité, Claudine, Hélène, Christel et Catherine pour leur aide (et les bons de commandes oligos toujours urgentissimes). Un grand merci à Hélène Brun et Claudie Offer du service commun de séquençage de l’IFR30 pour leur efficacité et leur gentillesse. Merci à Marie-Françoise Isaïa et Marie-Paule Henry pour leur expertise dans l’utilisation du cryotome, ou l’art de couper les poils en 4. Un merci tout particulier à Marie-Noëlle qui a partagé avec moi un coin de bureau, ainsi que quelques analyses de séquences... Je remercie nos collaborateurs du Genoscope et du centre de bioinformatique de Bordeaux pour leur aide dans la production et l’analyse des séquences. Merci aussi à Christian Vincent et Aurélien Rougemont pour leur aide dans la construction de la première base de données... et à Jim Kent pour son extraordinaire genome browser ! Merci aux enseignants de l’Université Paul Sabatier de m’avoir fait confiance pendant ces 3 ans de monitorat et cette dernière année d’ATER, Martine Briet, Pascale Belenguer, Gwenaëlle Fichant, Catherine Mathé et Pierre Ferrer. Merci infiniment à ce dernier de m’avoir encouragée à me diriger vers le DEA de biologie moléculaire. Merci à Michel Weber pour m’avoir acceptée au sein de sa formation doctorale, ainsi que pour l’aide qu’il m’a apportée dans l’utilisation du genome browser de l’UCSC. Merci enfin à Bruno Dagues et Bernadette Santoni du Centre d’Initiation à l’Enseignement Supérieur de Toulouse pour m’avoir permis de continuer à enseigner grâce à un support ATER spécifique. Merci à mesdames Casanova et Sutra, professeurs de biologie, respectivement au collège Victor Hugo de Lavelanet et au lycée de Mirepoix, de m’avoir transmis leur savoir et leur passion. Enfin et surtout, merci à mes proches de m’avoir supportée, au sens propre comme au sens figuré. Maman, Vital et Pierre-Guy, merci de votre patience. Charles, tu as traversé ces 4 années de thèse avec moi. Merci pour ton soutien et ta compréhension. Vous avez subi mes humeurs et mes états d’âme au quotidien, cette thèse n’existerait pas sans vous tous. Je dédie cette thèse à la mémoire de mon père. 6 Liste des abréviations aa : acides aminés ADN : Acide Désoxyribo-Nucléique ADNc : ADN Complémentaire AMP : Adénosine Mono-Phosphate AMPc : AMP cyclique ARN : Acide Ribo-Nucléique ARNm : ARN messager ATF : Activating Transcription Factor ATP : Adenosine Tri-Phosphate BAC : Bacterial Artificial Chromosome CCD : Charge-Coupled Device CDE : Complexe de Différenciation Epidermique CMH : Complexe Majeur d’Histocompatibilité CRE : cAMP Responsive Element Ct : threshold Cycle Dnase : deoxyribonuclease EBS : Epidermolyse Bulleuse Simple EDC : Epidermal Differentiation Complex EST : Expressed Sequence Tags FRET : Fluorescence Resonance Energy Transfer HT-ISH : High Throughput In Situ Hybridization GAPDH : GlycerAldehyde 3-Phosphate DesHydrogenase GFP : Green Fluorescent Protein GLGI : Generation of Longer cDNA fragments from SAGE tags for Gene Identification GPI : glycosylphosphatidylinositol HLA : Human Leukocyte Antigen IFAP : Intermediate Filament Associated Protein IL : interleukine IP3 : Inositol tri-phosphate kDa : kilodaltons LEF1 : Lymphoid enhancer-binding factor-1 LPS : lipopolysaccharide MAPK : Mitogen-Activated Protein Kinase pb : paire(s) de bases PCR : Polymerase Chain Reaction PGN : peptidoglycane RE : Réticulum Endoplasmique RT : Reverse Transcription SAGE : Serial Analysis of Gene Expression siRNA : small interfering RNA SNP : Single Nucleotide Polymorphism SSH : Suppression Subtractive Hybridization SST : Signal Sequence Trap Tm : melting Temperature TPA : phorbol ester 12-O-tetradecanoylphorbol-13-acetate TRE : TPA Responsive Element UV : rayons ultraviolets YAC : Yeast Artificial Chromosome 7 Résumé La fonction barrière de l’épiderme est assurée par sa partie la plus superficielle, la couche cornée, constituée de cornéocytes, des cellules très intercohésives, entourées d’un milieu extracellulaire riche en lipides. Les cornéocytes résultent de la cornification, une apoptose particulière. Les éléments constitutifs de ces cellules, ainsi que les enzymes qui régulent leur détachement pour permettre la desquamation, sont principalement synthétisés par les kératinocytes de la couche cellulaire sous jacente, la couche granuleuse. Le kératinocyte granuleux correspond non seulement au stade ultime de différenciation épidermique en termes de transcription et de traduction, mais aussi au point culminant de cette activité. Ce travail concerne l’étude du transcriptome du kératinocyte granuleux de l’épiderme humain, dans le but d’identifier de nouveaux gènes pour mieux comprendre la fonction de barrière et la régulation de la desquamation de l’épiderme normal. La mise au point d’une méthode d'incubations itératives à froid dans de la trypsine de lambeaux d’épiderme provenant de pièces opératoires, a permis de dissocier progressivement les kératinocytes épidermiques à partir de la couche basale pour obtenir des fragments majoritairement constitués de cornéocytes (sans activité transcriptionnelle) et de kératinocytes granuleux. En collaboration avec le Genoscope, 22 000 EST de kératinocytes granuleux ont été produits par la technique des ORESTES. Au total, 3387 gènes ont été identifiés dans les kératinocytes granuleux, dont une centaine environ codent pour des protéines hypothétiques. Parmi eux se trouvait un gène codant pour une protéine de fonction inconnue, la dermokine. Au cours de ce travail, 13 nouvelles isoformes de ce gène ont été mises en évidence.
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