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The Role of Chd7 & Chd8 Chromatin Remodelers in Oligodendrogenesis

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The Role of Chd7 & Chd8 Chromatin Remodelers in Oligodendrogenesis The role of Chd7 & Chd8 chromatin remodelers in oligodendrogenesis and (re)myelination Corentine Marie To cite this version: Corentine Marie. The role of Chd7 & Chd8 chromatin remodelers in oligodendrogenesis and (re)myelination. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2017. English. NNT : 2017PA066365. tel-01737394 HAL Id: tel-01737394 https://tel.archives-ouvertes.fr/tel-01737394 Submitted on 19 Mar 2018 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. Université Pierre et Marie Curie École doctorale CERVEAU, COGNITION et COMPORTEMENT Laboratoire Développement oligodendrocytaire et interactions neurovasculaires Institut du Cerveau et de la Moelle Epinière, Hôpital de la Pitié Salpêtrière UPMC UMR_S 975 - Inserm U 1127 - CNRS UMR 7225 - ICM THE ROLE OF CHD7 & CHD8 CHROMATIN REMODELERS IN OLIGODENDROGENESIS AND (RE)MYELINATION Par Corentine Marie Thèse soutenue le 29 septembre 2017 pour obtenir le titre de Docteur en neuroscience de l’Université Pierre et Marie Curie Devant un jury composé de : Pr Ann Lohof : Présidente du jury Pr. Michael Wegner : Rapporteur Dr. Elisabeth Traiffort : Rapportrice Dr Jean Livet : Examinateur Dr Jeannette Nardelli : Examinatrice Dr Carlos Parras : Directeur de Thèse 1 A mes regrettés grands-parents, Claude, Denise et Paul 2 3 Table of contents Remerciements ....................................................................................................................................... 8 Acronisms list ........................................................................................................................................ 10 Introduction .......................................................................................................................................... 12 Part I: Neural subtype determination .............................................................................................. 14 Part II: Oligodendrocyte Biology and Oligodendrogenesis Regulation........................................... 17 II.A – Oligodendrocytes are myelin-forming cells of the Central Nervous System .................... 17 II.A.1 – Oligodendrocytes are cells of the Central Nervous System ........................................ 17 II.A.2 – Oligodendrocytes are forming myelin sheath ............................................................. 17 II.A.3 – Myelin has different essential functions ..................................................................... 18 II.A.2.a - Rapid transmission ................................................................................................. 18 II.A.2.b – Plasticity ................................................................................................................ 20 II.A.2.c - Axonal support ....................................................................................................... 21 II.B – Multiple Sclerosis is characterized by a loss of myelin sheaths ......................................... 23 II.B.1 – Demyelination/Remyelination mechanism ................................................................. 23 II.B.2 – Evolution of the disease ............................................................................................... 24 II.C – Oligodendrogenesis and its transcriptional regulation ...................................................... 26 II.C.1 – Specification .................................................................................................................. 27 II.C.1.b – What is an OPC? .................................................................................................... 27 II.C.1.c – OPC functions ......................................................................................................... 28 II.C.1.d – OPC specification is highly regulated at the transcriptional level ....................... 29 II.C.2 - Differentiation ............................................................................................................... 33 II.C.2.a – Immature oligodendrocyte markers ..................................................................... 33 II.C.2.b – OPC differentiation regulation .............................................................................. 34 II.C.3 – Maturation/Myelination .............................................................................................. 38 II.C.3.a - Contact with axon .................................................................................................. 38 II.C.3.b - Wrapping ................................................................................................................ 39 II.C.3.c - Compaction ............................................................................................................. 40 II.C.3.c – Transcriptional regulation of myelination ............................................................ 42 II.C.4 – Remyelination ............................................................................................................... 46 II.C.4.a – Remyelination needs OPC differentiation ............................................................ 46 II.C.4.b – Remyelination models ........................................................................................... 47 II.C.4.c – Remyelination regulation ...................................................................................... 48 Part III: Mechanism of Transcription Initiation................................................................................ 49 III.A – From chromatin to gene expression .................................................................................. 49 4 III.A.1 – From DNA to chromatin .............................................................................................. 49 III.A.2 – Gene expression .......................................................................................................... 50 III.B – Regulatory Elements of transcription initiation ................................................................ 51 III.B.1 – Promoter ...................................................................................................................... 51 III.B.2 – Enhancer ...................................................................................................................... 52 III.C – Physical interaction between promoters and enhancers ................................................. 55 III.D – Regulation of interaction ................................................................................................... 57 III.D.1 – Transcription factors ................................................................................................... 57 III.D.2 – Cofactors ...................................................................................................................... 58 III.D.3 – Chromatin modifying factors ...................................................................................... 58 III.D.3.a – DNA methylation.................................................................................................. 58 III.D.3.b – Histone modifications .......................................................................................... 59 III.D.3.c – ATP-dependent alteration of chromatin ............................................................. 59 III.E – Methods to study chromatin .............................................................................................. 63 Part IV: Chd7 is a chromatin remodeling factors involved in CNS biology ..................................... 64 IV.A – CHD7 is involved in CHARGE syndrome ............................................................................ 64 IV.A.1 – What is CHARGE syndrome? ....................................................................................... 64 IV.A.2 – CHD7 mutations cause CHARGE syndrome ................................................................ 66 IV.A.3 – Other Syndromes involving CHD7 mutations ............................................................ 66 IV.B – Chd7 involvement in CNS biology ...................................................................................... 67 IV.B.1 – Expression of Chd7 in the brain .................................................................................. 67 IV.B.2 – Chd7 functions in the brain ......................................................................................... 67 IV.B.3 – Mechanisms of Chd7 function .................................................................................... 69 IV.C – Other members of Chd protein family .............................................................................. 71 IV.B.1 – Kismet is the Drosophila homologue of Chd7 ............................................................ 71 IV.B.2 – Chd Subgroup III .......................................................................................................... 71 IV.B.2.a – Chd8 .....................................................................................................................
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