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Transcriptional Networks of the Stress Responses in the Human Pathogen Candida Glabrata Antonin Thiebaut

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Transcriptional Networks of the Stress Responses in the Human Pathogen Candida Glabrata Antonin Thiebaut Transcriptional networks of the stress responses in the human pathogen Candida glabrata Antonin Thiebaut To cite this version: Antonin Thiebaut. Transcriptional networks of the stress responses in the human pathogen Can- dida glabrata. Biochemistry, Molecular Biology. Sorbonne Université, 2018. English. NNT : 2018SORUS485. tel-02613739 HAL Id: tel-02613739 https://tel.archives-ouvertes.fr/tel-02613739 Submitted on 20 May 2020 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. Sorbonne Université Institut de Biologie Paris-Seine- Team Structure of Genes Networks Doctoral school : Complexité du Vivant Doctoral Thesis Transcriptional networks of the stress responses in the human pathogen Candida glabrata Publicly defended on December 5th, 2018 Presented by : Under the supervision of : Antonin THIÉBAUT Prof. Frédéric DEVAUX Jury members : Cécile NEUVÉGLISE Examiner Sascha BRUNKE Reporter Nuno Gonçalo Pereira MIRA Reporter Christophe HENNEQUIN President iii For Andrée, Jean, Léon and Robert. v “I would rather have questions that can’t be answered than answers that can’t be questioned.” Richard Feynman vii Acknowledgements I would like to begin by thanking all my jury members : Sascha Brunke, Nuno Mira, Cécile Neu- véglise and Christophe Hennequin. Thank you for reading my work and giving me some of your time. I know it’s very valuable, given how hard it was to find a common date for my defense ! Fred, my PhD supervisor, thank you for all you have done for me, to begin with giving the opportunity to spend my PhD in your lab. I know how lucky I was to have this occasion and I don’t regret a single second taking the chance you offered me. I hope you feel the same. You taught me a lot, so, again, thank you for everything. I would also like to thank the rest of the team : Thierry and his legendary humor and hunger, coupled with the best lab tricks and advices ; Mathilde, for all your precious advices ; Pierre-Louis, for the fascinating talks on iron and the mind visits of Italy ; Médine, for putting up with me even if bothering you was one of my favorite hobbies and Gaëlle, you are not in the team per se, but you too taught me so much. including bioinformatics ! I am here today thanks to you. Thank you Aubin, Chloé and Sam, for the jokes, the escape rooms and the life at the lab. Antonio and Rossa, my favorite Italians. Nico and Stéphane, for the advices, the music and the loud discussions ! Marie-Laure and Fabienne, for all the lunches we spent together debating on so many topics. My family. You deserve much more than a “Thank you” for always supporting me, helping me and caring for me. Nina, thank you for always being there and changing my life. I would not have made it that far without you. And finally, thank you to all my friends Anne*, Antoine*, Brixme*, Célia*, Cookie*, Emeline*, Flo*, Gigi*, Jeanne*, Lancelot*, Machine, Paül*, Poulet*, Pygmée*, Thomas Linux*. (*alphabetical order, these great folks contributed equally to the friendship). Life would not be the same without you, your crazy ideas and our crazy parties ! Thank you all. This was a great adventure and it’s now time for me to open a new chapter. Or, as the great D.M. would say : "A tout le monde, à tous mes amis, je vous aime, je dois partir !". ix Abstract Candida glabrata is simultaneously a commensal of human gut and a pathogenic yeast with an increasing prevalence. It is often associated with fatal bloodstream infections, notably because of its ability to resist azole treatments, evade the immune system and easily colonize the human host. Also, it displays incredible abilities to adapt and resist adverse growth conditions. However, little is known about C. glabrata capacities to adapt and the underlying regulations. This assessment led to the implementation of the Candihub project. It aims to describe the mechanisms that allow C. glabrata to survive and thrive as a pathogen and has a focus on the transcriptional regulatory networks promoting the yeast strong resistance to stress. My PhD project was undertaken within the framework of Candihub. I tried to unravel the regulation networks associated to several transcription factors. These factors were chosen because of their key roles in controlling an array of stress responses : iron deprivation, iron excess, oxidative stress, osmotic stress... To achieve that goal, I performed high-throughput transcriptomic (microarrays) and genomic (ChIP -seq) analyses. This led to the construction of a wide network of interactions. Afterwards, I focused on smaller parts of this network. The first part tackled the role of the CCAAT-Binding Complex in respiration and iron homeostasis. The CBC is very conserved across the fungi. In S. cerevisiae, it controls cellular respiration, while in pathogenic fungi such as C. albicans, it controls the iron homeostasis. We showed that the CBC has a dual role in C. glabrata : it interacts with the regulatory subunit Hap4 to control respiration and it collaborates with Yap5 to act on iron homeostasis. The second part was based on the use of comparative transcriptomics to uncover unknown features of the iron starvation response of C. glabrata. We demonstrated the significance of Aft2 in response to iron starvation and we identified the regulatory network of Aft2. This revealed the involvement of genes responsible for ribosome rescue in the No GO Decay pathway, thus suggesting a link between iron homeostasis and the NGD. xi Résumé Candida glabrata est à la fois un commensal de l’homme et une levure pathogène dont la prévalence est en train d’exploser. Elle est souvent cause d’infections systémiques mortelles, notamment en raison de ses aptitudes à résister aux azoles, limiter sa détection par le système immunitaire et facilement coloniser l’hôte humain. Par ailleurs, elle possède une incroyable capacité à s’adapter et résister aux conditions de croissance défavorables. Cependant, on ne sait que très peu de choses sur les capacités d’adaptation de C. glabrata et les régulations qui les sous-tendent. Ce constat a mené à la création du projet Candihub, qui a pour but de décrire les mécanismes permettant à ce champignon de survivre et prospérer en tant que pathogène de l’homme. Candihub se focalise sur les réseaux de régulations transcriptionnelles favorisant la forte résistance au stress de Candida glabrata. Mon projet de thèse s’est déroulé dans le cadre de Candihub. J’ai révélé les réseaux de régulation associés à plusieurs facteurs de transcription. Ces facteurs ont été spécialement choisis en raison de leurs rôles clés dans le contrôle de diverses réponses au stress, telles que la carence en fer, l’excès de fer, les stress oxydatif et osmotique... Dans ce but, j’ai réalisé des expériences haut-débit de transcriptomique (puces à ADN) et génomique (ChIP-seq). Cela a mené à la construction d’un vaste réseau d’interactions. Je me suis ensuite concentré sur des sous-ensembles de ce réseau. La première partie a abordé le rôle du CCAAT-Binding Complex dans la respiration et l’homéostasie du fer. Le CBC est très conservé parmi les champignons. Dans S. cerevisiae, il contrôle la respiration cellulaire tandis que dans les champignons pathogènes tels que C. albicans, il gère l’homéostasie du fer. Nous avons montré que le CBC a un double rôle dans C. glabrata : il interagit avec la sous-unité régulatrice Hap4 pour contrôler la respiration et il collabore avec Yap5 pour réguler l’homéostasie du fer. La deuxième partie est fondée sur l’utilisation de la transcriptomique comparative pour découvrir de nouvelles propriétés de la réponse à la carence en fer de C. glabrata. Nous avons démontré l’importance d’Aft2 dans la réponse à la carence en fer et identifié le réseau de régulation d’Aft2. Cela a révélé le rôle de gènes normalement impliqués dans le sauvetage des ribosomes dans la voie du No Go Decay, ce qui suggère l’existence d’un lien entre l’homéostasie du fer et le NGD. xiii Contents Acknowledgements vii Abstract ix Résumé xi Contents xiii List of Figures xvii List of Tables xix List of Abbreviations xxi Introduction1 1 Candida glabrata, a yeast with many faces3 1.1 A hectic phylogenetic classification............................3 1.2 Close to Saccharomyces spp, far from Candida spp ?...................4 1.3 An "emerging" opportunistic pathogen...........................5 1.4 C. glabrata genome plasticity : a huge impact.......................8 1.5 Breaking C. glabrata clichés................................ 10 1.5.1 A commensal yeast ?................................ 10 1.5.2 An asexual yeast. for now............................ 13 2 Candida glabrata and the stress responses 15 2.1 A general response : the Environmental Stress Response (ESR).............. 15 2.2 Condition-specific stress responses............................. 19 xiv 2.2.1 Rox1, a mediator of response to hypoxia...................... 20 2.2.2 The oxidative stress response (OSR)........................ 21 2.2.3 The CCAAT-Binding Complex as a link between oxidative stress and respiration 27 2.2.4 The iron homeostasis is linked with respiration and oxidation........... 33 2.2.4.1 Response to iron-depleted media.................... 33 2.2.4.2 Response to iron-excess......................... 36 3 Candihub, the study of transcriptional networks of Candida glabrata stress responses 39 3.1 Networks : a model to represent connections between various elements.........
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