The Role of Acetylation in the Regulation of Antimicrobial Peptide Gene Expression in the Human Intestine Natalie Fischer
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The role of acetylation in the regulation of antimicrobial peptide gene expression in the human intestine Natalie Fischer To cite this version: Natalie Fischer. The role of acetylation in the regulation of antimicrobial peptide gene expression in the human intestine. Microbiology and Parasitology. Université Pierre et Marie Curie - Paris VI, 2014. English. NNT : 2014PA066276. tel-01371241 HAL Id: tel-01371241 https://tel.archives-ouvertes.fr/tel-01371241 Submitted on 25 Sep 2016 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. Unité de Pathogénie Microbienne Moléculaire THÈSE Présentée à L’Université Pierre et Marie Curie Ecole doctorale : ED515 « Complexité du Vivant » “The role of acetylation in the regulation of antimicrobial peptide gene expression in the human intestine” Par Natalie Fischer Thèse de doctorat de microbiologie Dirigée par Philippe Sansonetti Présentée et soutenue publiquement le 23 Septembre 2014 Devant un jury composé de : ARLET, Guillaume Professeur à l’UMPC (Président du jury) CERF-BENSUSSAN, Nadine DRCE INSERM (Rapporteur) AIT-SI-ALI, Slimane DR2 CNRS (Rapporteur) SANSONETTI, Philippe Professeur au Collège de France (Directeur de Thèse) SPERANDIO, Brice CR1 INSERM (Co-directeur de Thèse) Acknowledgements Acknowledgments First of all, I want to thank Philippe Sansonetti for flying me in from San Francisco to interview and giving me the change to conduct a thesis in his laboratory. I enjoyed very much the scientific discussions, which we shared over my project and his input in my work. Also I want to thank him for the excellent resources concerning working conditions as well as education, which are provided in his lab. I am very thankful to have had the chance to work in the presence of his scientific genius and kindness and I am grateful for his support throughout my thesis and afterwards. I want to thank Brice Sperandio for being my close supervisor for the past years. He guided me with the perfect balance of supervision, helped me settle in into the lab and project in the beginning, and later trusted me to walk on my own feet. I learned a lot from him, in the wet lab, but also concerning scientific writing and preparation of presentations. I am thankful that he respected my opinion and critics, encouraged my ideas and always had my best interest in mind. I am happy to say, that I think we made a good team and he really did a great job with me. I especially want to thank everybody who agreed to be on my thesis jury, for their time and interest in my work. Special thanks go to Nadine Cerf-Bensussan and Slimane Ait-Si-Ali for taking the time to read and correct my work and to Guillaume Arlet, who kindly accepted to be the president of my jury. I am very much looking forward to discuss my work with you! My time at the Sansonetti lab would not have been the same without the friendly atmosphere at PMM. I want to thank all my colleagues for their support, be it scientific discussions, technical help in the lab or mental with the beer after work. Especially I want to thank Emmanuel Sechet for his help in the last months, I could have never done all those Western Blots without him. Acknowledgements I would not have been here if it wasn’t for the EIMID ITN program, who gladly accepted me as a fellow. I enjoyed so much the international environment of this program. In this regard, I want to thank especially Marco Bargagna, who was always helpful and supportive, when it came to organizational things and deliverables. Also I want to thank the great group of EIMID fellows, who really made these years of my PhD special and with whom I enjoyed so many great times all around Europe. I also want to thank my friends in Paris, especially the 12:30 lunch gang. Everybody knows that science is a tough street and that especially during a PhD some breaking points are reached. Thankfully I had a great support from my friends here at Pasteur and I will never forget the times we shared in the ville de lumières. A special thanks goes to Mathieu, who shared a very special year with me, and who has always was a great support and source for laughter and good times. My family deserves a great round of applause for always supporting me during all my university education, morally and financially. I cannot thank you enough. I would not be here today if it wasn’t for my Mum, Meikel, my uncle Dieter and my dearly missed grandparents. This PhD title essentially goes to you! List of Abbreviations List of Abbreviations 1,25D3 – 1,25-dihydroxyvitamin D3 AD – Atopic dermatitis AMP – Antimicrobial peptide ANG4 – Angiogenin 4 AP1 – Activator protein 1 APC – Antigen-resenting cell APRIL – A proliferation-inducing ligand ARE – Apical recycling endosome ATF2 – Activating transcription factor 2 ATG16L1 – Autophagy related 16 like 1 ATP – Adenosine triphosphate BAFF – B-cell activating factor BMK – Big mitogen-activated protein kinase Brd4 – Bromodomain-containing protein 4 CAMP – Cathelicidin antimicrobial peptide CBP – cAMP-responsive element binding protein-binding protein CCL20 – CC-chemokine ligand 20 CCR6 – CC-chemokine receptor 6 CD – Crohn’s disease CDK9 – Cyclin-dependent kinase 9 CDRE – Caudal responsive element CFTR – Cystic fibrosis transmembrane conductance regulator CHD – Chromodomain-helicase-DNA-binding protein CNV – Copy number variation CNS1 – Conserved non-coding sequence 1 COPD – Chronic obstructive pulmonary disease CRAMP – Cathelin-related antimicrobial peptide CREB – Cyclic-AMP response element-binding protein CRS – Cryptdins-related sequence CTD – Carboxy‐terminal domain CTLA-4 – Cytotoxic T-lymphocyte antigen 4 CXCR4 – C-X-C chemokine receptor type 4 DC – Dendritic cell List of Abbreviations DEFB1 – Human beta defensin 2 DEFB2 – Human beta defensin 2 DEFB3 – Human beta defensin 3 DEFB4 – Human beta defensin 4 DNA – Deoxyribonucleic acid DNMT – DNA methyltransferases E. coli – Escherichia coli E. faecalis – Enterococcus faecalis EGFR – Epithelial growth factor receptor ER – Estrogen receptor ERE – Estrogen-responsive element ERK – Extracellular signal-regulated kinase FAE – Follicle-associated epithelia FliC – Flagella filament structural protein FOXO – Forkhead box transcription factor Foxp3 – Forkhead box P3 FRPL1 – Formyl peptide receptor-like 1 GALT – Gut-associated lymphoid tissue GAS – Group A Streptococcus GBS – Group B Streptococcus GCN5 – General control non-repressible synthesis 5 GNAT – GCN5-related N-acetyltransferases HAT – Histone acetyltransferase HBO1 – HAT bound to Orc1 hCAP18 – Human cationic antibacterial protein of 18 kDa HD 5 – Human alpha defensin 5 HD 6 – Human alpha defensin 6 HDAC – Histone deacetylase HDACi – HDAC inhibitor HDM – Histone demethylase HIF1 – Hypoxia inducible factor 1 HIP/PAP – Hepatointestinal pancreatic/pancreatitis‐ associated protein HIV – Human immunodeficiency virus HMT – Histone methyltransferase List of Abbreviations HNP – Human neutrophil peptide HOTAIR – Homeobox antisense intergenic RNA HPA axis – Hypothalamus–pituitary–adrenal axis H. pylori – Helicobacter pylori HSV – Herpes simplex virus HRE – HIF1 responsive element IAP – Intestinal alkaline phosphatase IBD – Inflammatory bowel disease IEC – Intestinal epithelial cell IEL – Intraepithelial lymphocyte IgA – Immunoglobulin A IgG – Immunoglobulin G IκBα – Inhibitor of NF-κB alpha IKK – IκB kinase IL8 – Interleukin 8 IL10 – Interleukin 10 IL1β – Interleukin 1 beta ILF – Isolated lymphoid follicles ILS – Insulin/insulin-like growth factor signaling Imd pathway – Immune deficiency pathway INF – Inflammatory gene IRAK – Interleukin-1 receptor-associated kinase IRF – Interferon response factor ISWI – Imitation SWI JDP – Jun dimerization protein JNK – c-Jun N-terminal kinases KCNN4 – Calcium-activated potassium channel protein 4 KDM2A – Lysine-specific demethylase 2A Lgr5 – Leucine-rich repeat-containing G-protein coupled receptor 5 lincRNA – Large multi-exonic intervening non-coding RNA LINoCR – LPS-inducible non-coding RNA L. monocytogenes – Listeria monocytogenes LPS – Lipopolysaccharide LSD1 – Lysine-specific demethylase 1 LTi cells – Lymphoid tissue inducer cells List of Abbreviations mAchR – Muscarinic acetylcholine receptor MAL – MYD88-adaptor-like protein MAMP – Microbe-associated molecular pattern MAPK – Mitogen-activated protein kinase M cells – Microfold cells MCP – Macrophage attractant protein MDP – Muramyl dipeptide MLN – Mesenteric lymph node MOF – Males absent on the first MORF – MOZ-related factor MOZ – Monocytic leukemia zinc finger protein MSK – Mitogen- and stress activated protein kinase MSV – Multi site variations M. tuberculosis – Mycobacterium tuberculosis MUC-2 – Mucin 2 MYD88 – Myeloid differentiation primary response 88 nAchR – Nicotinic acetylcholine receptor NCoR – Nuclear receptor corepressor NEMO – NF-κB essential modulator NFAT – Nuclear factor of activated T-cells NF-κB – Nuclear factor kappa B NK – Natural killer NLR – NOD-like receptor NOD – Nucleotide-binding oligomerization domain containing protein NuRD – Nucleosome remodeling deacetylase p300 – E1A-associated protein of 300 kDa P. aeruginosa – Pseudomonas