Impact of epigenome dysregulations on human diseases : study of Alzheimer’s disease models and SWI/SNF-dependent cancer models ; Impact des dérégulations de l’épigénome sur les maladies chez l’homme : études sur des modèles de la maladie d’Alzheimer et de cancers SWI/SNF-dépendants

Mammalian chromatin remodellers unwrap nucleosomal DNA to facilitate the binding of transcription factors (TFs). During my PhD, I explored in two distinct projects the molecular mechanisms which control chromatin organization and transcription: (1) In the first project, I re-explored a previous work suggesting that overexpression of histone deacetylase 2 (HDAC2) in the hippocampus of Alzheimer’s disease’s patients results in alterations of cognitive function. We detected a low amplitude overexpression of HDAC2 in the hippocampus of only one of the two mouse models of Alzheimer’s disease that we selected for our study. The low transcriptional impact of HDAC2 in these mouse models suggests a minor role of HDAC2 in Alzheimer’s disease. (2) In the second project, I studied the function of BRG1, the catalytic subunit of the SWI/SNF chromatin remodelling complex, which is frequently mutated in human cancers. First, we defined the nucleosomal and subnucleosomal organization of enhancers, using chromatin immunoprecipitation approaches combined to MNase-seq technique. We showed that at enhancers, BRG1 generates subnucleosomal particles which are targeted by different TFs in vivo. We also demonstrated that the OCT4 pioneer TF binds more efficiently to these subnucleosomal particles than to canonical nucleosomes. Based on these results, we propose a new model of organization and function for enhancers. ; Au niveau des éléments régulateurs du génome mammifère, les remodeleurs de la chromatine rendent accessible l’ADN empaqueté dans le nucléosome, permettant ainsi la liaison des facteurs de transcription (TFs). Au cours de ma thèse, j’ai exploré dans deux projets distincts les mécanismes moléculaires qui contrôlent l’organisation de la chromatine et la transcription : (1) Dans le premier projet, j’ai re-exploré des travaux antérieurs suggérant que la surexpression de l’histone desacetylase 2 (HDAC2) dans l’hippocampe provoquait l’altération des fonctions cognitives dans la maladie d’Alzheimer. Nous avons détecté une ...