Duhamel, Marianne (2007) Régulation épigénétique de l'expression du facteur de transcription hématopoïétique Aiolos et implication dans la leucémie lymphoïde chronique. PhD thesis Immunologie / Hématologie, INSERM U543, Immunologie Cellulaire et Tissulaire, AgroParistech 2007AGPT0031 p.382.

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Abstract

Le facteur de transcription Aiolos, membre de la famille des protéines à doigts de zinc de type Ikaros, joue un rôle important dans la différenciation des lymphocytes B.

Notre premier objectif a été de définir les mécanismes impliqués dans la régulation de la transcription du gène aiolos humain. Nous avons analysé la méthylation de l’îlot CpG d’Aiolos et les modifications de ses histones dans différentes lignées et cellules primaires. Nous avons observé une méthylation dense de l’ilot CpG, associée à des niveaux faibles de marques d’euchromatine (H3K4 di-/tri-méthylées, H3K9 acétylées) dans les lignées Aiolos négatives U937 et 1106mel, tandis que les cellules exprimant Aiolos présentaient les caractéristiques opposées. L’inhibition des Dnmt dans les U937 et 1106mel avec la 5-Aza-dC a entrainé une déméthylation de l’îlot CpG, associée à une augmentation des marques d’euchromatine et à une induction d’Aiolos. La répression d’Aiolos dans les monocytes et mélanocytes primaires a quant à elle été associée à une augmentation des H3K9me3 et H3K27me3, indépendamment de la méthylation de l’ADN.

Notre deuxième objectif était d’étudier l’implication d’Aiolos dans les syndromes lymphoprolifératifs des cellules B matures chez l’homme (leucémie lymphoïde chronique et autres lymphomes B). Nous avons démontré que les cellules B, saines et tumorales, exprimaient majoritairement le variant hAio1 (80%) et nous avons observé pour la première fois une augmentation globale des transcrits Aiolos dans la LLC, indépendamment des marqueurs pronostiques (ZAP-70, statut mutationnel des IgVH). Cette augmentation, confirmée au niveau protéique, semble indépendante des niveaux d’H3K4me3 et H3K9ace.

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Table of content

Table des illustrations 6

Abréviations 8





Avant-propos 11





Introduction 13

A. L’hématopoïèse : un processus complexe dont la désorganisation conduit à des pathologies encore méconnues 14

I. Les grandes étapes de l’hématopoïèse 14

1. Des produits aux fonctions variées 14

2. Au départ, une cellule souche hématopoïétique pluripotente 15

3. Un processus complexe de différenciation puis de maturation : l’exemple des cellules B 16

II. A l’échelle moléculaire : une cascade de facteurs de transcription 18

1. Depuis les cellules souches hématopoïétiques vers les progéniteurs lymphoïdes et myéloïdes : PU.1, GATA, Ikaros 18

2. Depuis les CLP vers les cellules B immatures : E2A, EBF, Pax5 20

3. Cellules B périphériques et formation du centre germinatif : Oct-2, OBF-1, NFκB, Aiolos, Bcl-6 21

4. Différenciation des cellules B des centres germinatifs en plasmocytes : Blimp-1 et XBP-1 22

III. Les conséquences d’un dérèglement de l’hématopoïèse : des proliférations malignes aux causes encore méconnues 23

1. La leucémie lymphoïde chronique B 24

2. Les lymphomes B non hodgkiniens 29



B. Aiolos, un facteur au fonctionnement complexe, impliqué dans la lymphopoïèse B 32

I. Structure et expression des protéines Ikaros et Aiolos 32

1. Une combinaison variable de doigts de zinc de type Cys2/His2, reconnaissant des domaines fonctionnels différents 32

2. Des profils d’expression distincts 33

II. Fonctions des protéines Ikaros et Aiolos in vivo 34

1. Ikaros affecte tous les lignages hématopoïétiques 34

2. Aiolos intervient dans la lymphopoïèse B 36

3. Quels sont les rôles des protéines Ikaros et Aiolos dans les hémopathies malignes humaines ? 38

III. Des protéines bifonctionnelles 40

1. Une localisation qui varie au cours du cycle cellulaire 40

2. Ikaros, un répresseur de la transcription 41

3. Ikaros, un activateur de la transcription 43

4. Qu’en est-il pour le facteur de transcription Aiolos ? 44

IV. Des modes de régulation peu documentés 45

1. Une influence du type d’isoforme et du nombre de sites de reconnaissance 45

2. Des modifications post-traductionnelles 46

3. Des effecteurs amont inconnus et des mécanismes complexes de régulation transcriptionnelle 46



C. L’épigénétique : une composante indispensable de la régulation transcriptionnelle 48

I. Des modifications épigénétiques de l’ADN et des histones 48

1. La méthylation de l’ADN 49

2. Des modifications covalentes des histones 50

3. Des modifications non covalentes 54

II. Impact des modifications épigénétiques sur la régulation transcriptionnelle 55

1. Deux types d’environnements chromatiniens 55

2. Chromatine et assemblage du complexe d’initiation de la transcription 56

3. L’impact des modifications covalentes des histones et de l’ADN sur la régulation transcriptionnelle 57

III. Implication des mécanismes de régulation épigénétique au cours de la différenciation hématopoïétique 61

1. Epigénétique et hématopoïèse 61

2. Déséquilibre épigénétique et cancer 62



D. Objectifs du travail de thèse 64







Chapitre I : Une régulation épigénétique de la transcription du gène aiolos qui diffère entre lignées tumorales et cellules primaires 65

I. Préambule 66

II. Matériel et Méthodes 67

III. Résultats 71

1. Un îlot CpG de 342 pb encadre le site d’initiation de la transcription du gène aiolos 71

2. Le traitement, avec des agents inhibiteurs des Dnmt (5-Aza-dC) et/ou des HDAC (TSA), induit une augmentation des transcrits Aiolos 71

3. Dans les lignées cellulaires, l’expression d’Aiolos est corrélée à une déméthylation de l’îlot CpG 73

4. La méthylation in vitro de l’îlot CpG d’aiolos bloque l’activité transcriptionnelle du promoteur 74

5. Des profils distincts de modifications des histones 75

6. La déméthylation du promoteur aiolos avec la 5-Aza-dC induit une augmentation localisée des marques d’euchromatine active 76

7. L’inhibition d’Aiolos dans les cellules primaires fait appel à des mécanismes indépendants de la méthylation du promoteur 77

IV. Discussion 78

1. Méthylation de l’ADN : un rôle dans les lignées tumorales mais pas dans les cellules primaires 78

2. Modifications des histones : un rôle prépondérant dans les cellules primaires et dans les lignées Aiolos positives 81



Chapitre II : Une augmentation de l’expression d’Aiolos dans la LLC qui ne semble pas liée à des modifications épigénétiques 84

I. Préambule 85

II. Matériel et Méthodes 86

III. Résultats 89

1. Les isoformes dominantes négatives d’Aiolos sont minoritaires chez les donneurs sains comme chez les patients atteints de LLC ou de LNH 89

2. hAio 1 et hAio 4 représentent plus de 80% des isoformes Aiolos exprimées par les lymphocytes B, indépendamment de leur caractère cancéreux ou non 90

3. Les transcrits Aiolos sont augmentés dans la LLC, par rapport aux donneurs sains 91

4. La surexpression d’Aiolos dans la LLC ne semble pas dépendre de modifications épigénétiques au promoteur aiolos 92

IV. Discussion 93







Discussion/Perspectives 97

1. Isoformes Aiolos et leucémogénèse 99

2. Les cibles d’Aiolos ? Une intervention dans la transduction des signaux émis par le BCR et dans le contrôle de l’apoptose 101

3. Qui régule le régulateur ? Une composante génétique indissociable des mécanismes épigénétiques 102







Bibliographie 106







Annexes 131

Annexe 1 : Aiolos et Ikaros 132

Annexe 2 : Aiolos et Epigénétique 144

Annexe 3 : Aiolos et LLC 179

Annexe 4 : Autres publications 190

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