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, Régulation Transcriptionnelle du Locus Igh Lors de la Commutation Isotypique Résumé en Français Au cours du développement de la moelle osseuse, les cellules B assemblent un ensemble divers de récepteurs de cellules B fonctionnels (BCR) par recombinaison V(D)J, qui se diversifie davantage au cours de la réponse immunitaire dans les organes lymphoïdes secondaires par deux mécanismes : l'hypermutation somatique (HS)

, V) des gènes des chaînes lourdes et légères, modifiant ainsi l'affinité du BCR pour son antigène apparenté. La CI remplace l'isotype exprimé d'IgM à IgG, IgE ou IgA par un événement de recombinaison au niveau du locus de la chaîne lourde des Ig (IgH), HS introduit des mutations ponctuelles dans la région variable

L. Hs and . La, CI sont tous deux déclenchés par AID, une enzyme qui génère des mutations dans les régions V et des cassures double brin de l'ADN au niveau des régions de commutation (S) au cours de l'HS et la CI, respectivement. En raison de son potentiel mutagène, AID doit être étroitement régulée et ciblée. Cependant, les mécanismes moléculaires précis qui sous

, Figure 1 : (A) Représentation schématique du locus IgH murin

C. I. La and . Le-recrutement-d'aid-couplé-À-la-transcription-dans-le-locus-igh, L'activation transcriptionnelle du locus IgH pendant la CI est contrôlée par l'enhancer Eµ et par la région régulatrice 3'RR [3, 4]. Étant donné que les régions de recombinaison donneuse et accepteuse (S) peuvent être distantes de 200 kb, la CI nécessite également des interactions à longue portée. En effet, il a été montré que le locus IgH dans les cellules B au repos forme une boucle impliquant la région Sµ du donneur, l'enhancer Eµ et le récepteur 3'RR, et que la région S de l'accepteur est également recrutée dans la

, Les mécanismes et les facteurs impliqués dans la formation et le maintien de boucles d'ADN, ainsi que leur rôle dans la diversification des anticorps

, sont recrutés de manière dynamique dans les enhancers du locus IgH et la région accepteuse au cours de la CI et qu'ils ont un effet sur l'efficacité de la transcription stérile, la formation de boucles et la CI [6]. Nous avons constaté que pendant la CI, les enhancers Eµ et 3'RR interagissent de manière dynamique avec une région située, Notre laboratoire a récemment montré que Med1 et Med12, deux sous-unités du complexe Mediator

, Cette région est non seulement liée par les sous-unités Med1 et Med12 de Mediator, mais porte en outre de marques de la chromatine caractéristiques des enhancers

, Comme la transcription seule ne peut expliquer le ciblage et l'action d'AID sur les gènes des Ig, d'autres facteurs, tels que la structure de la chromatine

, Sur la base de ces observations, mon hypothèse de travail est que la région 1E est un nouvel enhancer putatif du locus IgH et qu'elle pourrait jouer un rôle dans la régulation de la recombinaison V(D)J, de la HS et de la CI chez les cellules B. L'objectif principal de ma thèse est de caractériser fonctionnellement le rôle de la région 1E récemment décrite lors de la diversification des anticorps

, Par ailleurs, comme indiqué précédemment, la boucle et la transcription sont nécessaires pour la CI. Plusieurs études ont indiqué que la transcription était le processus déclencheur qui induit la boucle dans d'autres modèles, vol.12

. Ainsi, un autre objectif de ma thèse est de déterminer si la transcription stérile des régions S est suffisante pour induire la CI

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