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Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau

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Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau Searching for novel peptide hormones in the human genome Olivier Mirabeau To cite this version: Olivier Mirabeau. Searching for novel peptide hormones in the human genome. Life Sciences [q-bio]. Université Montpellier II - Sciences et Techniques du Languedoc, 2008. English. tel-00340710 HAL Id: tel-00340710 https://tel.archives-ouvertes.fr/tel-00340710 Submitted on 21 Nov 2008 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. UNIVERSITE MONTPELLIER II SCIENCES ET TECHNIQUES DU LANGUEDOC THESE pour obtenir le grade de DOCTEUR DE L'UNIVERSITE MONTPELLIER II Discipline : Biologie Informatique Ecole Doctorale : Sciences chimiques et biologiques pour la santé Formation doctorale : Biologie-Santé Recherche de nouvelles hormones peptidiques codées par le génome humain par Olivier Mirabeau présentée et soutenue publiquement le 30 janvier 2008 JURY M. Hubert Vaudry Rapporteur M. Jean-Philippe Vert Rapporteur Mme Nadia Rosenthal Examinatrice M. Jean Martinez Président M. Olivier Gascuel Directeur M. Cornelius Gross Examinateur Résumé Résumé Cette thèse porte sur la découverte de gènes humains non caractérisés codant pour des précurseurs à hormones peptidiques. Les hormones peptidiques (PH) ont un rôle important dans la plupart des processus physiologiques du corps humain. Ce sont de petites protéines sécrétées générées après clivage de précurseurs plus larges codés par le génome. Dans la première partie de la thèse, l’on introduit des algorithmes, basés sur les chaînes de Markov cachées (HMM), qui vont nous permettent de modéliser les séquences protéiques des précurseurs à hormones peptidiques. On montre que l’on peut dégager des caractéristiques particulières au niveau de la séquence chez ce groupe de protéines et l’on s’attarde en particulier sur la modélisation de deux signaux toujours présents chez ces protéines, les peptides signaux et les sites de clivage par les prohormones convertases. On présente ensuite des algorithmes qui prennent en compte le degré de conservation des résidus le long d’alignements de protéines orthologues. On montre que ces nouveaux algorithmes améliorent de manière significative les résultats obtenus à l’aide des algorithmes classiques. Enfin, après lancement de l’algorithme sur des données de protéomes, l’on dégage une liste de candidats dont certains ont pu être étudiés au laboratoire. La deuxième et la troisième partie de la thèse présentent les conclusions que l’on peut tirer des données de Western blot relatives aux profils de sécrétion et de découpage (processing) de chacun des deux candidats les plus prometteurs, « spexine » et « augurine ». On présente des données d’expression sur la souris (hybridation in situ, immunohistochimie,…) que l’on a récemment obtenues sur ces nouvelles hormones peptidiques potentielles ainsi que des données fonctionnelles sur la « spexine ». En conclusion, l’on avance des hypothèses quant aux fonctions de ces deux protéines. Si les fonctions de ces nouveaux peptides nous sont encore inconnues, leur expression chez la souris, tant au niveau de l’ARN messager que de la protéine, révèle des pistes qui devraient soulever un intérêt certain chez les spécialistes du domaine des peptides. Enfin, dans la quatrième et dernière partie de la thèse, l’on présente pour quatre autres candidats (dont on n’a pu mener une étude approfondie) des données préliminaires d’expression de gène et de sécrétion in vitro après transfection de l’ADN codant pour ces protéines dans des cellules issues de lignées cellulaires pancréatiques. Mots clés : hormones peptidiques, neuropeptides, chaines de Markov cacahees, analyse de sequences proteiques. - 2 - Abstract Abstract The goal of my thesis was to discover novel peptide hormones (PH) in the human genome. Peptide hormones (PH) are an important class of molecules that are involved in a broad range of normal and pathological physiological processes. PH are small secreted proteins that are processed from larger proteins, called precursors. In the first part of the thesis I introduce hidden Markov models (HMM)-based algorithms that allow for the modelling of those PH precursor sequences. This leads me to derive models of some of their well-known characteristic features, including signal peptides and prohormone convertase cleavage sites. Next, I make use of orthology information and modify the HMM algorithms so that the HMM can incorporate a conservation score that is calculated along protein sequence alignments. I show that this idea brings significant improvements in the quality of predictions and I conclude the chapter by drawing a list of potential candidate peptide hormones that was obtained by running the HMM algorithms on genome-wide protein sequence data. In the second and third part of the thesis I present data on the most interesting candidates that we named “spexin” and “augurin”. I show in vitro subcellular localization, secretion and processing of those proteins after transfection of their coding DNA into endocrine cells. I then show mRNA and protein in vivo expression data in the mouse for those two proteins, and present functional data on spexin. I conclude both chapters by making some speculations on the functional significance of those two proteins. In the fourth part of the thesis I present data on the expression, secretion and processing of four extra candidate peptide hormones. - 3 - Acknowledgments Acknowledgments-Remerciements-Ringraziamenti Merci avant tout à mon directeur de thèse au LIRMM Olivier Gascuel, pour m’avoir lancé dans la direction des HMM, et pour avoir cru en moi jusqu’au bout. Un grand merci à mes prestigieux rapporteurs Hubert Vaudry et Jean-Philippe Vert pour avoir accepté mon invitation improvisée. Je remercie également Jean Martinez pour m’avoir fait l’honneur de présider mon jury de thèse. Warmest thanks to Nadia for bringing me there in the first place, for her amazing personality, for putting her trust in me, for her energy, infectious enthusiasm, her generous research financial support and for cutting me slack at the beginning of my PhD! My special thanks go to Cornelius Gross, who was essential throughout my PhD, for his kind support and understanding, for giving me confidence at the beginning, for his great ideas and communicative passion for science. I am indebted to Ewan Birney for accepting to be in my EMBL TAC, for supervising my bioinformatics work, for hosting me at the EBI at the beginning of my PhD and being so supportive all along. I am grateful to the generous EMBL PhD program which gave me this opportunity, especially Anne Ephrussi for her understanding. Thank you to all my colleagues at the EMBL who helped me along the way with their advices and good mood. Special thanks to our precious histologist Emerald Perlas for his refreshing enthusiasm, wonderful in situs and histochemistry and for inspiring discussions. Thank you to the Gross lab for their (love and) affection, Tiago Ferreira, Luisa Lo Iacono, Enrica Audero, Valeria Carola, Olga Ermakova, Theodoris Tsetsenis, Giovanni Frazzetto, Apar Jain and Amaicha Depino. Thank you also to the members of Nadia’s lab for their help and good nature, Nadine Winn, Paschalis Kratsios, Esfir Slonimski, Arianna Nenci, Lieve Temermann,, Catarina Catela, Tommaso Nastasi, Marion Huth, Katik Salimova Foteini Mourkioti, Michele Pelosi, Christian Fasci, Eli Reuveni, Marianne Hede (E-tidsskrifter, really useful!), Ekaterina Salimova, Pascal Te Welscher, Katia Semenova. From the EMBL and collaborators of the EMBL I owe much to David Tosh (for the fantastic insulin-packed RIN cell line), Enrique Lara-Pezzi (my first PCR… sigh…), Tiago Ferreira (for your warm company and laughs in the late hours at the lab and especially for letting me ride your motorino), Paschalis Kratsios (for this precious aliquot of 20mM dNTPs), Shin Kang (without you I would still be trying to clone that 56 blunt sequence into the TA vector), Walter Witke (if only the FLAG wasn’t acidic!), generally the Witke lab for being so generous in letting me have whatever I want from their lab, Pietro Pilo-Boyl (calcetto, cell fractionation, political and philosophical discussions), Enrica Audero (il capo for organising everything and her precious help), Arianna Nenci (for becoming the genespring expert so I can work on my project). Special thanks to Nadine Winn, Luisa Lo Iacono, Tiago Ferreira and Elke Kurz for many good memories. - 4 - Acknowledgments I’d like to thank also to Mark Carter, Jose Gonzalez, Augusto De Paolis, the caretakers and the admininistration for running things so smoothly at the EMBL. Grazie a Roberta Possenti per la sua simpatia e i preziosi consigli e segreti su come si deve lavorare con i peptidi! Grazie anche a Cinzia Severini per i suoi dati eccezionali. Merci aux thésards (et ex-thésards) du LIRMM pour leur accueil chaleureux, tout particulièrement Jean-Baka Domelevo-Entfellner et Raluca Uricaru pour leur précieuse aide logistique ainsi que leur amitié. Dans cette catégorie, je remercie également Nicolas Philippe, ainsi que Samuel Blanquart, Cécile Bonnard et Celine Scornavacca. Un grand merci au monsieur HMM du LIRMM, Laurent Bréhélin, pour sa disponibilité et ses suggestions pertinentes. Merci enfin à Catherine Larose de l’Ecole doctorale Biologie-Santé pour m’avoir si gentiment aidé dans mes démarches administratives. Merci à mes précédents mentors Christian Saguez, Robin Munro et Georg Casari, pour m’avoir accordé leur confiance. Merci à mes potes d’Arrayscout qui m’ont initié aux joies de la programmation java, Nicolas Rodriguez, Charles Girardot, Andreas Buness et Sylvie Lefranc. Merci aussi au team bioinfo d’Epigène, Guillaume Kerboul, Eric Perche et David Monteau qui ont accompagné mes premiers pas dans la vie active.
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