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Genetic and Epigenetic Determinants of Thrombin Generation Potential : an Epidemiological Approach Maria-Ares Rocanin-Arjo

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Genetic and Epigenetic Determinants of Thrombin Generation Potential : an epidemiological approach Maria-Ares Rocanin-Arjo To cite this version: Maria-Ares Rocanin-Arjo. Genetic and Epigenetic Determinants of Thrombin Generation Potential : an epidemiological approach. Génétique humaine. Université Paris Sud - Paris XI, 2014. Français. NNT : 2014PA11T067. tel-01231859 HAL Id: tel-01231859 https://tel.archives-ouvertes.fr/tel-01231859 Submitted on 21 Nov 2015 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. UNIVERSITÉ PARIS-SUD ÉCOLE DOCTORALE 420 : SANTÉ PUBLIQUE PARIS SUD 11, PARIS DESCARTES Laboratoire : Equip 1 de Unité INSERM UMR_S1166 Genomics & Pathophysiology of Cardiovascular Diseases THÈSE DE DOCTORAT SANTÉ PUBLIQUE - GÉNÉTIQUE STATISTIQUE par Ares ROCAÑIN ARJO Genetic and Epigenetic Determinants of Thrombin Generation Potential: an epidemiological approach. Date de soutenance : 20/11/2014 Composition du jury : Directeur de thèse : David Alexandre TREGOUET DR, INSERM U1166, Université Paris 6, Jussieu Rapporteurs : Guy MEYER PU_PH, Service de pneumologie. Hôpital européen Georges Pompidou Richard REDON DR, Institut thorax, UMR 1087 / CNRS UMR 6291 , Université de Nantes Examinateurs : Laurent ABEL DR, INSERM U980, Institut Imagine Marie Aline CHARLES DR, INSERM U1018, CESP Al meu pare (to my father /à mon père) Your genetics load the gun. Your lifestyle pulls the trigger. Mehmet Oz Reserve your right to think, for even to think wrongly is better than not to think at all. Hypatia If you want to know about thrombin- measure thrombin" HC Hemker Aknowledgements / Remerciemets / Agraïments C'est incroyable, mais malgré ce que je craignais au début, ces trois ans ont passé très vite ! Il y a trois ans, déjà, j'ai commencé ma première journée dans l'unité U937 (maintenant UMR_S1166). Tout juste 5 jours avant, j'arrivais avec mes deux valises. Je m’en souviens encore : Moi, attendant le bus 351 à l’extérieur du terminal de CDG. Une dame m'avait alors demandé comment se rendre au centre de Paris. Puis elle m'avait dit: "Je viens pour visiter Paris, vous aussi ?". Et je lui avais répondu : "Non, je viens pour y vivre, je vais faire un doctorat.". Deux heures plus tard et une bonne route à travers les banlieues parisiennes, je débarquais sur la place Gallieni pour retrouver celui qui serait mon colocataire et que je ne connaissais pas encore. Quels premiers jours ! Que d’émotions ! La veille de commencer ma thèse, à l’occasion d’Halloween, j'étais allée au cinéma Le Champo, où j’avais passé la nuit devant 3 films d’horreur. En sortant au petit matin, avec mon premier croissant et mes nouvelles connaissances, nous avions décidé de rentrer à pied à travers les rues de Paris. Quelle belle promenade. Il n’y avait personne et en arrivant à la Seine nous avions découvert Notre Dame illuminée par le soleil levant et toute pour nous. Que Paris est belle ! J’ai aussi des souvenirs de mes premiers jours au labo et notamment des 3-4 alertes incendie que nous avions eues en trois jours. Je me souviens de la première fois que j'ai entendu la sirène des pompiers, en pensant, "C'est grave ? Qu'est-ce qu'il faut faire ? C'est une alerte ? Que font les autres ? Rien. Tranquilles... Donc, ok c'est rien ". Je me rappelle aussi de la petite souris qui habitait dans la cuisine. Maintenant, à la fin de ma thèse, nombre d’expériences et de moments vécus, qui m’ont appris aussi bien professionnellement qu’humainement, se rappellent à moi. Je tiens d’abord à remercier François Cambien et Laurence Tiret pour m'avoir accueillie tout au début au sein de l'ancienne unité U937 intitulée "Génomique Cardiovasculaire". Je voudrais aussi remercier l'ensemble du jury d’avoir accepté de consacrer de leur temps pour évaluer ce travail : mes deux rapporteurs, le Professeur Guy Meyer et Monsieur Richard Redon, pour leur relecture profonde et leurs critiques ; je remercie aussi mon examinateur Monsieur Laurent Abel et mon examinatrice et présidente de jury Madame Marie-Aline Charles. Je remercie le professeur Pierre Emmanuel Morange pour son important apport dans ce travail et pour avoir mis en place l'étude MARTHA, une étude très puissante sans laquelle je n'aurais pu faire ma thèse. De même, je remercie France Gagnon et les members de l'étude des "Three City" pour m'avoir permis d'utiliser des données issues de leur cohorte. Je remercie également l'ensemble de l'unité, ceux qui sont là actuellement ainsi que ceux qui y sont passés que ce soit pour un bon moment ou tout simplement de passage. Votre sympathie, votre complicité et votre soutien constant m'ont permis de me sentir intégrée et m’ont donné la sensation d’appartenir à une petite "famille" : Merci aux filles, aux nouvelles Beata et Maguelonne ainsi qu’aux deux Marie-Laure. Merci Carole pour ta joie et ton effort pour que je fasse du sport. Merci Claire pour m’avoir fait découvrir le reblochon et pour m’avoir permis de me maintenir en contact avec la biologie. Vielen danke Ulli (ma belle!!) pour tout: les fêtes, les instants de complicité et pour avoir partagé avec moi tous ces moments. Zahia, pour ta sympathie constante et pour partager avec moi le goût pour le café crème. Grazie mille Veronica pour ton soutien constant. Je vous remercie Ewa, Laurence et Hervé pour nos conversations dans la cuisine. Merci Badreddine pour tes agréables "salut" dans le couloir et "bon appétit" en passant par la cuisine. Merci Nadjim et Lyamine pour être toujours si galants. Merci François (le roux, juif, irlandais,...) pour tes cours de "français des jeunes". Merci Nathalie pour nos discussions politiques et éthiques et pour rendre le monde administratif moins effrayant et plus accessible. Merci Henri, revenu juste pour la fin, pour tes blagues provocatrices et ton ironie. Merci beaucoup à mon compagnon de "fatigue" et bon ami, Dylan (Methylman), qui est toujours dispo pour faire un petit "break" pour se détendre et discuter mais surtout pour m'aider avec les machines. Merci à Maxime même si nous n’avons jamais été en même temps dans l'unité. Merci à Raphaele, Ricardo, Vinhou, Nico, Marie et Guillaume (Boby), pour leur sympathie, leur joie et leur bonne humeur, pour les activités "afterwork chez Jimmy", pour les questions "Nico", pour les "hotdogs chilenos", pour l'hippodrome, pour le cours d'escalade ou le poulet au curry thaï de Vinh! Et aussi merci aux stagiaires (oompa loompas) Lynn, Bathou, Yasmine, Evangelia, Francesca, "Doudou", Pauline, Bastien, pour leurs croissants, Romain qui est passé au coté "compagnon de fatigues" et merci aussi aux canadiens avec qui je garde une amitié précieuse, Martin et Jessica. Je remercie vivement mes copines de bureau: Marine et Sophie, pour avoir égayé mon quotidien, pour avoir répondu à toutes mes questions, pour votre précieuse aide en relisant ce mémoire, pour m’avoir "supportée" dans les derniers mois difficiles, pour nos moments comiques en racontant nos expériences personnelles mais aussi gourmands en parlant de recettes. Vous allez me manquer. Ce sera bizarre de ne plus vous voir après ces 3 ans ! Enfin je veux remercier plus particulièrement mon directeur de thèse, David-Alexandre Trégouët pour sa confiance en moi, surtout au début quand il ne me connaissait pas, en m'aidant pour ma première inscription à la faculté, pour la recherche d'appartement et pour les démarches administratives. Merci beaucoup d’avoir accordé ta confiance à une biologiste sans expérience pour réaliser ce projet. Merci pour ton très bon encadrement, pour ton aide en tout moment au cours de ces trois ans et pendant l'écriture de ma thèse. Merci pour avoir été patient avec ma façon de faire (lui très organisé et moi j’ai une tendance au désordre), et pour ton exigence, qui m’a certes valu certains moments difficiles à endurer, mais m’a permis de me surpasser, de m'organiser et d’avoir le travail que je présente ici. Je vais désormais retourner à mes origines et continuer dans ma langue natale, le Catalan, pour mieux exprimer mes remerciements à mes amis et à ma famille: Sou moltes persones que també heu aportat el vostre granet de sorra i m'heu permès arribar fins aquí. Tots els meus companys de grups anteriors: Magda, Georgios, Marc, Robert, Esther, Mireia, i Pedro, els primers en ensenyar-me i formar-me com a investigadora i amb els que encara conservo una boníssima amistat. Després, les pipetes Raquel, Sonia, Biel i Miquel Soute, pels nostres dinars, esmorçars, cafès, birres i moments a la cabanya i els tecles Angel, Alfonso, Anna i Leonor que em van començar a mostrar en els "lab-meetings" el món dels bioinformàtics i estadístics. Moltíssimes gràcies, José Manuel Soria, per dornar-me l'oportunitat de fer la tesi a Paris, interessant-te i demanant per beques als teus col·laboradors. Encara recordo el moment en que m'ho vas comunicar: em vas trucar perquè m'havia demanat festa per poder saltar en paracaigudes. Dues emocions fortes en un mateix dia. Recordo com vaig estar pensant el què hauria de fer. Vull reiterar les gràcies a Sonia per la temporada que va estar a Paris, en la qual em va ajudar molt al inici de la meva estada que sempre és dura, 6 mesos on vam compartir converses post dinar, moments explosius de desesperació,fins i tot cases.
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  • Spatial Sorting Enables Comprehensive Characterization of Liver Zonation

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    ARTICLES https://doi.org/10.1038/s42255-019-0109-9 Spatial sorting enables comprehensive characterization of liver zonation Shani Ben-Moshe1,3, Yonatan Shapira1,3, Andreas E. Moor 1,2, Rita Manco1, Tamar Veg1, Keren Bahar Halpern1 and Shalev Itzkovitz 1* The mammalian liver is composed of repeating hexagonal units termed lobules. Spatially resolved single-cell transcriptomics has revealed that about half of hepatocyte genes are differentially expressed across the lobule, yet technical limitations have impeded reconstructing similar global spatial maps of other hepatocyte features. Here, we show how zonated surface markers can be used to sort hepatocytes from defined lobule zones with high spatial resolution. We apply transcriptomics, microRNA (miRNA) array measurements and mass spectrometry proteomics to reconstruct spatial atlases of multiple zon- ated features. We demonstrate that protein zonation largely overlaps with messenger RNA zonation, with the periportal HNF4α as an exception. We identify zonation of miRNAs, such as miR-122, and inverse zonation of miRNAs and their hepa- tocyte target genes, highlighting potential regulation of gene expression levels through zonated mRNA degradation. Among the targets, we find the pericentral Wingless-related integration site (Wnt) receptors Fzd7 and Fzd8 and the periportal Wnt inhibitors Tcf7l1 and Ctnnbip1. Our approach facilitates reconstructing spatial atlases of multiple cellular features in the liver and other structured tissues. he mammalian liver is a structured organ, consisting of measurements would broaden our understanding of the regulation repeating hexagonally shaped units termed ‘lobules’ (Fig. 1a). of liver zonation and could be used to model liver metabolic func- In mice, each lobule consists of around 9–12 concentric lay- tion more precisely.