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HSF1 Promotes TERRA Transcription and Telomere Protection Upon Heat Shock

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HSF1 Promotes TERRA Transcription and Telomere Protection Upon Heat Shock THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTÉ UNIVERSITÉ GRENOBLE ALPES Spécialité : CSV/ Biologie du développement-Oncogenèse Arrêté ministériel : 7 août 2006 Présentée par Sivan KOSKAS Thèse dirigée par Claire VOURC’H et Codirigée par Virginie FAURE Préparée au sein de l’Institut pour l’Avancée des Biosciences site Albert Bonniot Dans l'École Doctorale Chimie et Science du vivant HSF1 promotes TERRA transcription and telomere protection upon heat shock Thèse soutenue publiquement le 27 Septembre 2016 Devant le jury composé de : Pr. Stefan NONCHEV Professeur, IAB, Grenoble (Président) Dr. Valérie MEZGER Directrice de recherche, Paris Diderot (Rapporteur) Dr. Patrick, REVY Directeur de recherche, Paris Descartes (Rapporteur) Dr. Anabelle DECOTTIGNIES Directrice de recherche, Institut de Duve, Bruxelles (Membre) Dr. Vincent GELI Directeur de recherche, CRCM, Marseille (Membre) Pr. Claire VOURC’H Professeur, IAB, Grenoble (Membre) Dr. Virginie FAURE Enseignant-chercheur, IAB, Grenoble (Membre) Table of contents Table of contents ............................................................................................................ 1 Abstract ......................................................................................................................... 6 Résumé .......................................................................................................................... 7 Abbreviations list ........................................................................................................... 8 INTRODUCTION ............................................................................................................ 11 Chapter I|Stress and HSF1 ............................................................................................. 12 I. Cellular stress and heat shock response (HSR) .................................................... 12 I. 1. Historical discovery of the HSR .......................................................................... 12 I. 2. Triggers of the HSR ............................................................................................. 13 I. 3. Deleterious effects of cellular stress .................................................................. 15 I. 4. Overview of the HSR .......................................................................................... 18 a/ Heat shock proteins-coding genes activation ................................................ 18 b/ Modulation of other protein coding genes ................................................... 18 c/ Upregulation of non-coding genes ................................................................ 19 d/ Epigenetic modifications ............................................................................... 19 II. Heat Shock Factor 1 (HSF1) ................................................................................. 21 II. 1. Key actor of the cellular HSR .............................................................................. 21 II. 2. Structure ............................................................................................................ 22 a/ DNA Binding Domain (DBD) ........................................................................... 22 b/ Trimerization Domain (HR-A/B) ..................................................................... 23 c/ Regulatory domain (RD) ................................................................................ 24 d/ Spontaneous trimerization domain HR-C ...................................................... 24 e/ Transactivation domain (TAD) ....................................................................... 25 II. 3. Regulation of HSF1 ............................................................................................. 25 a/ Activation ...................................................................................................... 27 b/ Repression ..................................................................................................... 29 III. HSF1 targets and functions in the HSR ................................................................ 32 III. 1. HSE: Heat Shock Elements ................................................................................. 32 III. 2. Chaperones ........................................................................................................ 33 1 III. 3. Heterochromatin ................................................................................................ 36 a/ Constitutive heterochromatin ....................................................................... 36 b/ Nuclear stress bodies (nSBs) .......................................................................... 37 c/ Activation of pericentric satIII ncRNA ............................................................ 37 IV. Other functions of HSF1 ...................................................................................... 40 IV. 1. Fertility and development .................................................................................. 40 IV. 2. Ageing and cancer .............................................................................................. 42 Chapter II|Telomeres and TERRA .................................................................................. 45 I. Telomeres .......................................................................................................... 45 I. 1. Chromatin: general introduction ....................................................................... 45 I. 2. Chromatin at telomeres ..................................................................................... 49 a/ Genomic sequences ....................................................................................... 49 b/ Heterochromatin status ................................................................................ 51 I. 3. Telomere capping ............................................................................................... 54 a/ The T-loop structure ...................................................................................... 54 b/ Shelterin complex .......................................................................................... 55 c/ CST complex .................................................................................................. 56 d/ Vital functions of telomere capping .............................................................. 57 e/ End replication problem ................................................................................ 58 I. 4. Telomere maintenance mechanisms ................................................................. 60 a/ Telomerase .................................................................................................... 60 b/ ALT ................................................................................................................. 63 II. Telomere transcripts – TERRA ............................................................................. 64 II. 1. Biogenesis .......................................................................................................... 64 II. 2. TERRA transcriptional regulation ....................................................................... 67 a/ By promoter methylation .............................................................................. 67 b/ By associated epigenetic histones modifications .......................................... 67 c/ By telomere length and shelterin .................................................................. 69 II. 3. TERRA attributed functions ................................................................................ 70 a/ Telomere length regulation ........................................................................... 71 b/ Telomeric heterochromatin formation ......................................................... 73 c/ Telomere Replication .................................................................................... 74 2 d/ Processing of uncapped telomeres ............................................................... 75 e/ Implications in immunity cancer and disease ................................................ 76 THE PhD PROJECT’S ORIGINS AND OBJECTIVES ............................................................... 78 I. The project’s origins ........................................................................................... 79 II. Objectives .......................................................................................................... 81 RESULTS ....................................................................................................................... 83 Chapter I|HSF1 impact on TERRA upon HS ..................................................................... 84 I. Control of HSF1 knock down model .................................................................... 84 II. HSF1 is required for TERRA accumulation upon HS ............................................. 86 II. 1. HSF1-dependenet accumulation of global TERRA upon HS ............................... 86 II. 2. HSF1-dependent accumulation of chromosome-specific TERRA upon HS ........ 89 III. HSF1-dependent dynamics of TERRA foci upon HS .............................................. 89 IV. Subtelomeric promoters regions constitute new HSF1 targets ............................ 93 IV. 1. Potential HSF1-binding sites at human subtelomeres ....................................... 93 IV. 2. In vivo HSF1 enrichment at subtelomeres upon HS ..........................................
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