Dynamique chromatinienne lors de l'activation des enhancers au cours de la différenciation cellulaire

Abstract : Cell differentiation relies on a coordinated and finely regulated transcriptional regulation involving the recruitment of cell-type transcription factors (TFs) on genomic regions called enhancers. Some of these TFs, named pioneer factors (PFs), are able to bind to condensed chromatin and favour enhancer transition from an inactive to a primed state, thus facilitating the binding of other TFs and enhancer activation. Therefore, lineage commitment is associated to the engagement of PFs at enhancers where the chromatin structure undergoes architectural modifications related to the set up of specific marks. These include, the monomethylation of the lysine 4 of the histone H3 (H3K4me1), the acetylation of the lysine 27 of the histone H3 (H3K27ac) or cytosine modifications (5-methylcytosine, 5mC; 5-hydroxymethylcytosine, 5hmC). The 5hmC base is an intermediate in the process of active demethylation coming from the oxidation of the 5mC by the Ten Elven Translocation (TET) enzymes and can itself be further oxidized in 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), two bases which are then replaced by cytosines through the Base Excision Repair mechanism. Nevertheless, due to its stability and its ability to bind some specific proteins, 5hmC might also play specific roles. Previous works already highlighted a link between the recruitment of PFs and cytosine modifications. However, the involvement of the methylation/demethylation processes in the spatio-temporal regulation of the priming and activation of enhancers has not yet been characterized. In this context, the aim of this study was to define the role of cytosine modifications (5mC and 5hmC) during the activation of enhancers bound by PFs. For this, we analyzed the implication of cytosine methylation and demethylation processes on enhancer priming and activation by using DNA methyltransferases or TET inhibitors. In addition, we identified the dynamics of enhancer priming and activation genome-wide during neural differentiation, in relation to the presence of 5hmC. The results allow us to propose a scheme of enhancer activation in which DNA methylation/demethylation dynamics play an essential role in the chromatin structure of these regulatory elements.
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Elise Mahé. Dynamique chromatinienne lors de l'activation des enhancers au cours de la différenciation cellulaire. Biologie cellulaire. Université Rennes 1, 2016. Français. ⟨NNT : 2016REN1B056⟩. ⟨tel-02174509⟩

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