L'INFLUENCE DU RECEPTEUR A L'OESTROGENE a SUR LA HORMONO-DEPENDENTS

L'INFLUENCE DU RECEPTEUR A L'OESTROGENE a SUR LA
DYNAMIQUE CHROMATINIENNE DANS LES CANCERS DU SEIN
HORMONO-DEPENDENTS
PAR
AMY SVOTELIS
These soumis au Departement de biologie
pour I'obtention du diplome de philosophiae doctor (Ph.D.)
FACULTE DES SCIENCES
UNIVERSITE DE SHERBROOKE
Sherbrooke, Quebec, Canada, mai 2011

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Le27mai2011
lejury a accepte la these de Madame Amy Svotelis
dans sa version finale.
Membres du jury
Professeur Nicolas Gevry
Directeur de recherche
Departement de biologie
Professeur Luc R. Gaudreau
Codirecteur de recherche
Departement de biologie
Professeur Daniel Lafontaine
Membre
Departement de biologie
Professeur Andre Tremblay
Membre externe
Universite de Montreal, CHU Ste-Justine
Professeur Viktor Steimle
President rapporteur
Departement de biologie

TABLE OF CONTENTS
ABSTRACT iv
RESUME VI
ACKNOWLEDGEMENTS VIII
LIST OF ABBREVIATIONS X
LIST OF TABLES XII
LIST OF FIGURES XIII
CHAPTER 1 1
I. INTRODUCTION 1
1.1. THE EUKARYOTIC GENOME 1
/. /. /. Structure of the eukaryotic genome 2
1.1.2. Chromatin remodelling via A TP-dependent complexes 5
1.1.3. Incorporation ofhistone variants into the nucleosome 7
1.1.3.1. The his tone variant H2A.Z 10
1.1.4. Post-translational h is ton e modifications 14
1.2. CHROMATIN ARCHITECTURE AND REGULATABLE GENE EXPRESSION 19
1.2.1. RNA Polymerase II transcription of genes 20
1.2.2. Transcription factor mediated gene regulation 22
1.2.3. Chromatin architecture at regulatory elements 24
1.2.4. Mechanisms of transcriptional activation and roles ofH2A.Z in gene expression 25
1.2.5. Gene silencing and the resolution of poised chromatin states 29
1.3. NUCLEAR RECEPTOR MEDIATED TRANSCRIPTION 34
1.3.1. ERa-regulated gene expression 37
1.3.1.1. The ERa genomic pathway 37
1.3.1.2. Non-classical ERa pathways 40
1.3.2. ERa-dependent breast cancer and anti-estrogen resistance 41
1.4. RESEARCH PROJECT AND OBJECTIVES 44
ii

CHAPTER II 47
II. REGULATION OF GENE EXPRESSION AND CELLULAR PROLIFERATION BY
HISTONEH2A.Z 47
II.l. PREAMBLE 47
H.2. MANUSCRIPT 49
CHAPTER HI 78
III. H2A.Z OVEREXPRESSION PROMOTES CELLULAR PROLIFERATION OF BREAST
CANCER CELLS 78
111.1. PREAMBLE 78
111.2. MANUSCRIPT 80
CHAPTER IV 101
IV. H3K27 DEMETHYLATION BY JMJD3 AT A POISED ENHANCER OF ANTI-
APOPTOTIC GENE BCL2 DETERMINES ERa LIGAND-DEPENDENCY 101
IV. 1. PREAMBLE 101
IV.2. MANUSCRIPT 103
CHAPTER V 148
V. DISCUSSION 148
V.l. ERa MODULATION OF CHROMATIN SIGNATURES AFFECTS THE CELL CYCLE 149
V.2. THE ROLE OF EPIGENETIC SIGNATURES IN ANTI-ESTROGEN RESISTANCE 153
V.3. GENERAL CONCLUSIONS AND PERSPECTIVES 156
VI. REFERENCES 159
in