Functional characterization of alternative splice variants of the Drosophila GATA transcription factor serpent containing either one or two zinc finger domains Douaa Moussalem To cite this version: Douaa Moussalem. Functional characterization of alternative splice variants of the Drosophila GATA transcription factor serpent containing either one or two zinc finger domains. Genetics. Université Paul Sabatier - Toulouse III, 2020. English. NNT : 2020TOU30138. tel-03162582 HAL Id: tel-03162582 https://tel.archives-ouvertes.fr/tel-03162582 Submitted on 8 Mar 2021 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. THÈSE En vue de l’obtention du DOCTORAT DE L’UNIVERSITÉ DE TOULOUSE Délivré par l'Université Toulouse 3 - Paul Sabatier Présentée et soutenue par Douaa MOUSSALEM Le 12 octobre 2020 Titre : Functional characterization of alternative splice variants of the Drosophila GATA transcription factor Serpent containing either one or two zinc finger domains. Ecole doctorale : BSB - Biologie, Santé, Biotechnologies Spécialité : GENETIQUE MOLECULAIRE Unité de recherche : CBD - Centre de Biologie du Développement Thèse dirigée par Marc HAENLIN et Dani OSMAN Jury M. David CRIBBS, Président Mme Annarita MICCIO, Rapporteure Mme Kyra CAMPBELL, Rapporteure M. Samir MERABET, Rapporteur M. Marc HAENLIN, Directeur de thèse M. Dani OSMAN, Co-directeur de thèse “I dedicate this work to my parents, who have always supported and encouraged me to achieve my goals. This work is also dedicated to my adorable sisters: Amani, Mariam and Aya, who are an inexhaustible source of motivation, love and strength.” 1 Acknowledgments First, I would like to thank Drs. Annarita Miccio, Kyra Campbell, Samir Merabet and David Cribbs, for accepting to be part of my thesis jury. I also profoundly thank my supervisors Dani Osman and Marc Haenlin, the CBD (Centre de Biologie du développement), its director Fabienne Pituello, the doctoral school BSB (Biologie-Santé-Biotechnologies) and its director Philippe Valet, for giving me the opportunity to do my PhD. I would like to express my sincere gratitude to Dr. Dani Osman, who returned to Lebanon from Switzerland five years ago. When Dani arrived at the Lebanese University with his tiny flies, he sparked my curiosity to know everything about what was happening in this wonderful organism. I was impressed by his positivity, his intelligence and his supportive soul. One of the best days of my life was when Dani accepted to be my thesis co-director. He subsequently helped me to get my Lebanese fellowship, and then he introduced me via skype to Marc and Lucas. But he didn’t stop there, his support and care are endless. I would now like to thank Dr. Marc Haenlin for accepting me in his group and for helping me get third and fourth year fellowships from the UPS (Université Paul Sabatier). Thank you, Marc, for helping me to get settled in France once I had arrived, and thank you for being around every day. Thank you for your support and guidance throughout my work, the scientific discussions that we had, and also for correcting my thesis manuscript. I am also grateful to the greatest researcher and the queen of Genetics, Dr. Vanessa Gobert. Thank you, Vanessa, for always being so active and dynamic. Thank you for staying around and for listening to all of the scientific questions from the PhD students. You definitely transmitted your passion for science. And thank you for reading and correcting my thesis manuscript and for helping me every single time I needed help. 2 I also thank the GATA factor enthusiast Benoit Auge for his technical help in the lab, the awesome colleague Thomas Genais for being so kind and active throughout my entire thesis period, Delhia Gigan for her energy and sense of humour, and the graduated PhD student Aichun Chen for sending us every year greeting cards from China. I thank our neighbours, the Zebrafish people, Patrick’s group members, for the joy and the sense of humour that they spread. Special thanks to Patrick Blader and Pascale Dufourcq who have reminded me several times that I should take a break and not only think about work. And thanks to Pascale again, for giving me a ride home each time we finished late in lab. I am also thankful to Alain Vincent and Michele Crozatier’s group members for the useful discussions that we had during all these years, for sharing materials, and also for the group spirit. Special thanks to Caroline Monod for reading and correcting my thesis manuscript and for always being a gentle person. My deep gratitude to François Payre for his kindness and care. My sincere thanks to Philippe Valenti for all the useful advice that he gave me. I absolutely thank the entire Payre group for being so friendly and active. Of course, I thank Alice Davy and Cathy Soula’s group. Thanks also to the dearest funniest colleague Mohammad Fawal, and the kindest David Ohayon. I would like to express my deep gratitude to all the members of the CBD, including the groups of Fabienne Pituello, Bertrand Bénazéraf, Muriel Boube, Andreas Merdes and Eric Théveneau. Special thanks to Gwenaelle Juffroy and Marie Pelletier and everyone working in the secretariat, you are the sweetest and the kindest. Also, thanks to Julien Favier and Amélie Destenabes for fly medium preparation. Thanks again to Julien for always finding solutions to my requests. Thanks to the service informatique, Laurent Sanchou and Franck Cressent, 3 especially for providing me with a PC. I used it throughout my entire thesis period. And thank you Franck, for always helping me. Finally, thank you all for being part of my four years of thesis. Seeing you was a constant source of pleasure and encouragement. Your kind words and your passion for science helped generate an uplifting environment every day. I will always remember the CBD outings, which were full of learning and funny times. I wish all of you, years of exciting research, interesting results, health and happiness. 4 Content Content ................................................................................................................................................... 5 Abstract .................................................................................................................................................. 9 Titre/Résumé ........................................................................................................................................ 11 Foreword .............................................................................................................................................. 14 List of abbreviations ............................................................................................................................ 16 List of figures ....................................................................................................................................... 21 Chapter I. Introduction ...................................................................................................................... 24 (A) Introduction to GATA transcription factors................................................................................ 25 1- Molecular structure of GATA transcription factors .................................................................. 25 2- GATA factors interact with other transcriptional regulators..................................................... 29 a- GATA factors interact with different partners ...................................................................... 29 b- GATA factors interact with cofactors of the Friend of GATA family .................................. 32 3- GATA mutations are associated to human diseases .................................................................. 37 a- Mutations in GATA factors induce the formation of numerous pathologies ........................ 37 b- Point mutations in GATA zinc fingers provoke human diseases whose severity depends on the position and the nature of the mutation ............................................................................... 38 (B) GATA factors mode of action ..................................................................................................... 41 1- Mechanistic functions of GATA factors ................................................................................... 41 a- GATA and transcriptional activation .................................................................................... 41 b- GATA and transcriptional repression ................................................................................... 42 c- GATA and chromatin looping ............................................................................................... 44 2- Dynamic functions of GATA factors ........................................................................................ 45 a- GATA as pioneer factors ....................................................................................................... 45 b- The GATA switch ................................................................................................................