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ii Faculte de Medecine et des Sciences de la Sante Departement d'anatomie et de biologie cellulaire Les facteurs transcriptionnels CUXl et HNF4a sont impliques dans le renouvellement de I'epithelium intestinal, les maladies inflammatoires intestinales et le cancer colorectal Par M. Mathieu Darsigny Departement d'anatomie et de biologie cellulaire These presentee a la Faculte de Medecine et des Sciences de la Sante En vue de l'obtention du grade de Philosophiae Doctor (Ph.D.) en Biologie Cellulaire These evaluee par Francois Boudreau (Universite de Sherbrooke) Nathalie Rivard (Universite de Sherbrooke) Raymund Wellinger (Universite de Sherbrooke) Maxime Bouchard (Universite McGill) S£PTErA6££ 3.01G Library and Archives Bibliotheque et 1*1 Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your We Votre reference ISBN: 978-0-494-75079-7 Our file Notre reference ISBN: 978-0-494-75079-7 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library and permettant a la Bibliotheque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par I'lnternet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans le loan, distribute and sell theses monde, a des fins commerciales ou autres, sur worldwide, for commercial or non­ support microforme, papier, electronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette these. Ni thesis. Neither the thesis nor la these ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent etre imprimes ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformement a la loi canadienne sur la Privacy Act some supporting forms protection de la vie privee, quelques may have been removed from this formulaires secondaires ont ete enleves de thesis. cette these. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. 1+1 Canada Ill A LA MEMOIRE DE CEUX QUI M'ONT QUITTE AVANT QUE LA BIOMEDECINE PUISSE LES SAUVER Ma marraine, HELENE Mon grand-pere, GEORGES Mon pere, BERNARD IV MAIS SURTOUT, A CEUX DONT LA QUALITE DE VIE PEUT ENCORE ETRE AMELIOREE BRIGITTE (CD) DIANNA (UC) GABRIEL (CD) KELLY (CD) JONATHAN (IBS) SIMON (CD) VINCENT (UC) V LE MEILLEUR MO YEN D'AVOIR UNE BONNE IDEE EST D'EN AVOIR BEAUCOUP (LINUS PAULING) vi TABLE DES MATIERES TABLE DES MATIERES vi LlSTE DES FIGURES xii LlSTE DES TABLEAUX xiv LlSTE DES TRAVAUX XV LlSTE DES ABREVIATIONS xvi SOMMAIRE xix INTRODUCTION 1 1. Le systeme digestif 2 1.1 L'organogenese du tube digestif 2 1.2 Le renouvellement de 1'epithelium intestinal 4 1.3 Former et maintenir les cryptes 7 1.4 La differenciation des cellules epitheliales intestinales 8 2. L'immunite mucosale intestinale 12 2.1 Les structures lymphoides associees a 1'intestin 13 2.2 L'immunite innee : role de l'epithelium 15 2.3 L'immunite innee : role des leucocytes 19 2.4 Les macrophages : Un statut particulier au sein de 1'intestin 21 2.5 L'immunite adaptative : education et tolerance 22 3. Les maladies inflammatoires intestinales 25 3.1 La maladie de Crohn et la colite ulcereuse 25 3.2 Etiologie 26 Vll 4. Le cancer colorectal 28 4.1 Cancers familiaux 29 4.2 Mutations somatiques 29 4.3 Le cancer associe a la colite 31 5. Les facteurs de transcription 32 6. Le facteur de transcription CUX1 34 6.1 Structure genetique et proteique 34 6.2 Modes transcriptionnels 36 6.3 Regulation de I'expression et regulation post-traductionnelle 36 6.4 L'identification des premiers genes cible 38 6.5 Regulation du cycle cellulaire 39 6.6 Regulation de l'inflammation 41 6.7 Regulation de la migration cellulaire 42 7. Le facteur de transcription HNF4a 43 7.1 Decouverte et caracteristiques 43 7.2 Caracteristiques de la proteine 44 7.3 Les isoformes d'HNF4a 44 7.4 Distribution de son expression durant le developpement et chez I'adulte 45 7.5 Regulation transcriptionnelle d 'HNF4A 47 7.6 Regulation post-traductionnelle 48 7.7 Cofacteurs 48 7.8 Ligands endogenes et exogenes 51 7.9 Les fonctions et genes cibles d'HNF4a 52 7.10 HNF4a et metabolisme 54 8. Hypotheses, objectifs et methodes 55 8.1 CUX1 56 8.2 HNF4a 57 viii RESULTATS 59 MANUSCRIT 1 60 CUXL TRANSCRIPTION FACTOR IS INDUCED IN INFLAMMATORY BOWEL DISEASE AND PROTECTS AGAINST EXPERIMENTAL COLITIS 60 1.1 Auteurs et affiliations 61 1.2 Contributions 61 1.3 Resume 62 1.4 Abstract 63 1.5 Introduction 65 1.6 Materials and methods 67 1.7 Results 72 1.8 Discussion 83 1.9 Acknowledgments 87 1.10 References 88 MANUSCRIT 2 95 HEPATOCYTE NUCLEAR FACTOR 4a CONTRIBUTES TO AN INTESTINAL EPITHELIAL PHENOTYPE IN VITRO AND PLAYS A PARTIAL ROLE IN MOUSE INTESTINAL EPITHELIUM DIFFERENTIATION.. 95 2.1 Auteurs et affiliations 96 2.2 Contributions 96 2.3 Resume 97 2.4 Abstract 98 2.5 Introduction 99 2.6 Materials and methods 102 2.7 Results 107 2.8 Discussion 119 2.9 Acknowledgments 123 2.10 References 123 IX MANUSCRIT3 131 LOSS OF HEPATOCYTE-NUCLEAR-FACTOR-40C AFFECTS COLONIC ION TRANSPORT AND CAUSES CHRONIC INFLAMMATION RESEMBLING INFLAMMATORY BOWEL DISEASE IN MICE 131 3.1 Auteurs et affiliations 132 3.2 Contributions 132 3.3 Resume 134 3.4 Abstract 135 3.5 Introduction 136 3.6 Materials and methods 138 3.7 Results 143 3.8 Discussion 154 3.9 Acknowledgements 158 3.10 Supplementary data 159 3.11 References 174 MANUSCRIT4 179 HEPATOCYTE-NUCLEAR-FACTOR-40C PROMOTES NEOPLASIA IN MICE AND PROTECTS AGAINST THE PRODUCTION OF REACTIVE OXYGEN SPECIES 179 4.1 Auteurs et affiliations 180 4.2 Contributions 180 4.3 Resume 182 4.4 Abstract 183 4.5 Introduction 184 4.6 Materials and methods 187 4.7 Results 191 4.8 Discussion 201 4.9 Acknowledgements 206 4.10 Supplementary data 207 4.11 References 217 X DISCUSSION 227 1. CUX1 228 1.1 Observations initiales 228 1.2 Permeabilite epitheliale 229 1.3 Regulation de l'expression de CUX1 231 1.4 Migration cellulaire 233 1.5 Proliferation 235 1.6 Experiences futures 236 CONCLUSION GENERALE(CUXI) 238 2. HNF4a et la regulation de la cytodifferenciation intestinale 240 2.1 Le maintien du renouvellement epithelial a l'age adulte 240 2.2 Axe entero-insulaire 245 2.3 Ouverture 249 3 FfNF4a et la regulation de l'inflammation 250 3.1 Comparaison des modeles 250 3.2 Colite spontanee 250 3.3 Initiation de la colite spontanee 253 3.4 Metabolisme du butyrate 256 3.5 Aspect endocrinien et Mil 257 3.6 Regulation de l'expression d'HNF4a 257 3.7 Cancer associe a la colite 260 4. HNF4a dans le cancer colorectal 261 4.1 Retour sur l'hypothese 261 4.2 Interpretation des resultats 261 4.3 Le stress oxydatif. 263 4.4 HNF4a et TP53 dans le cancer colorectal 265 XI 4.5 Deregulation des promoteurs PI et P2 268 4.6 Hnf4a et p53 chez les animaux Hnf4aAIEC 269 4.7 Regulation du metabolisme durant le cancer 273 4.8 Chimioresistance et efflux des drogues 277 4.9 Experiences futures 278 4.10 Therapeutique 281 4.11 Modele propose 282 4.12 Ouverture 285 CONCLUSION GENERALE (HNF4 A) 286 REMERCIEMENTS 288 REFERENCES 291 ANNEXES 351 xii LlSTE DES FIGURES INTRODUCTION Figure 1 4 Figure 2 6 Figure 3 6 Figure 4 11 MANUSCRITl 60 THE CUXl TRANSCRIPTION FACTOR IS INDUCED IN INFLAMMATORY BOWEL DISEASE AND PROTECTS AGAINST EXPERIMENTAL COLITIS 60 Figure 1 73 Figure 2 75 Figure 3 77 Figure 4 78 Figure 5 79 Figure 6 80 Figure 7 82 Figure 8 83 MANUSCRIT2 95 HEPATOCYTE NUCLEAR FACTOR 4a CONTRIBUTES TO AN INTESTINAL EPITHELIAL PHENOTYPE IN VITRO AND PLAYS A PARTIAL ROLE IN MOUSE INTESTINAL EPITHELIUM DIFFERENTIATION.. 95 Figure 1 109 Figure 2 110 Figure 3 112 Figure 4 115 Figure 5 117 Figure 6 118 xiii MANUSCRIT3 131 LOSS OF HEPATOCYTE-NUCLEAR-FACTOR-4a AFFECTS COLONIC ION TRANSPORT AND CAUSES CHRONIC INFLAMMATION RESEMBLING INFLAMMATORY BOWEL DISEASE IN MICE 131 Figure 1 143 Figure 2 145 Figure 3 146 Figure 4 148 Figure 5 150 Figure 6 151 Figure 7 153 MANUSCRIT4 179 HEPATOCYTE-NUCLEAR-FACTOR-4a PROMOTES NEOPLASIA IN MICE AND PROTECTS AGAINST THE PRODUCTION OF REACTIVE OXYGEN SPECIES 179 Figure 1 192 Figure 2 194 Figure 3 195 Figure 4 196 Figure 5 198 Figure 6 199 Figure 7 200 DISCUSSION 227 Figure 5 239 Figure 6 284 ANNEXE 351 Figure 7 353 xiv LiSTE DES TABLEAUX INTRODUCTION Tableau 1 47 Tableau 2 50 MANUSCRIT 1 MANUSCRIT 2 MANUSCRIT 3 Tableau SI 159 Tableau S2 160 Tableau S3 170 Tableau S4 172 MANUSCRIT 4 Tableau SI 207 Tableau S2 214 DISCUSSION ANNEXE Tableau 3 351 Tableau 4 352 XV LlSTE DES TRAVAUX MANUSCRIT 1 THE CUXl TRANSCRIPTION FACTOR IS INDUCED IN INFLAMMATORY BOWEL DISEASE AND PROTECTS AGAINST EXPERIMENTAL COLITIS 60 MANUSCRIT 2 HEPATOCYTE NUCLEAR FACTOR 4a CONTRIBUTES TO AN INTESTINAL EPITHELIAL PHENOTYPE IN VITRO AND PLAYS A PARTIAL ROLE IN MOUSE INTESTINAL EPITHELIUM DIFFERENTIATION.
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  • Supplemental Figure and Table Legends

    Supplemental Figure and Table Legends

    Supplemental figure and table legends Supplementary Figure 1: KIAA1841 is well conserved among vertebrates. NCBI HomoloGene pairwise alignment scores of human KIAA1841 sequence compared to other vertebrate orthologs. Supplementary Figure 2: µ-germline transcripts (GLT) and AID mRNA expression are not affected by overexpression of KIAA1841. Splenic B cells were isolated from wild-type mice, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841. Levels of µ-GLT and AID mRNA were determined at 72h post-infection by RT-qPCR, and normalized to -actin mRNA and the pMIG control. The mean of three independent experiments +/- SD is shown. NS, p = not significant, p 0.05, two-tailed paired student’s t-test. Supplementary Figure 3: Overexpression of untagged and Xpress-tagged KIAA1841 does not affect cell proliferation. Splenic B cells were isolated from wild-type mice, stimulated with LPS+IL4, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841 or Xpress (Xp)-tagged KIAA1841. Cells are labeled with seminaphthorhodafluor (SNARF) cell tracking dye and SNARF intensity was measured at 0h, 24h, and 48h after retroviral infection. Histograms of transduced cells (GFP+) for pMIG control, KIAA1841 and Xp-KIAA1841 were superimposed at each time point. Three independent retroviral infection experiments are shown. Supplementary Figure 4: Sequence alignment of the putative SANT domain of KIAA1841 with the SANT domain of SWI3. Alignment was performed using ClustalOmega; *, conserved residue, :, strongly similar residues, ., weakly similar residues. Numbers indicate amino acid residues in each sequence. Helix 3, which has been reported to be important for the chromatin remodeling function of SWI3 (Boyer et.
  • Table S2.A-B. Differentially Expressed Genes Following Activation of OGR1 by Acidic Ph in Mouse Peritoneal Macrophages Ph 6.7 24 H

    Table S2.A-B. Differentially Expressed Genes Following Activation of OGR1 by Acidic Ph in Mouse Peritoneal Macrophages Ph 6.7 24 H

    Table S2.A-B. Differentially expressed genes following activation of OGR1 by acidic pH in mouse peritoneal macrophages pH 6.7 24 h. A. Gene List, including gene process B. Complete Table (Excel). Rank Symbol Full name Involved in: WT/KO (Reference: Gene Card, NCBI, JAX, Uniprot, Ratio unless otherwise indicated) 1. Cyp11a1 Cholesterol side chain cleavage Cholesterol, lipid or steroid metabolism. enzyme, mitochondrial (Cytochrome Catalyses the side-chain cleavage reaction of P450 11A1) cholesterol to pregnenolone. 2. Sparc Secreted acidic cysteine rich Cell adhesion, wound healing, ECM glycoprotein (Osteonectin, Basement interactions, bone mineralization. Activates membrane protein 40 (BM-40)) production and activity of matrix metalloproteinases. 3. Tpsb2 Tryptase beta-2 or tryptase II (trypsin- Inflammatory response, proteolysis. like serine protease) 4. Inhba Inhibin Beta A or Activin beta-A chain Immune response and mediators of inflammation and tissue repair.2-5 5. Cpe Carboxypeptidase E Insulin processing, proteolysis. 6. Igfbp7 Insulin-like growth factor-binding Stimulates prostacyclin (PGI2) production and protein 7 cell adhesion. Induced by retinoic acid. 7. Clu Clusterin Chaperone-mediated protein folding, positive regulation of NF-κB transcription factor activity. Protects cells against apoptosis and cytolysis by complement. Promotes proteasomal degradation of COMMD1 and IKBKB. 8. Cma1 Chymase 1 Cellular response to glucose stimulus, interleukin-1 beta biosynthetic process. Possible roles: vasoactive peptide generation, extracellular matrix degradation. 9. Sfrp4 Secreted frizzled-related protein 4 Negative regulation of Wnt signalling. Increases apoptosis during ovulation. Phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake. 10. Ephx2 Bifunctional epoxide hydrolase Cholesterol homeostasis, xenobiotic metabolism by degrading potentially toxic epoxides.