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Caractérisation de la diversité des sites de fixation des protéines du groupe Polycomb chez la Drosophile

Abstract : Polycomb group (PcG) complexes were initially discovered in Drosophila as transcriptionnal repressors of homeotic genes. To date, we know that they are involves in a large pleithora of biological processes including the maintenance of stem cells plasticity, differentiation, X chromosome inactivation and imprinting. PcG complexes are highly conserved from Drosophila to Humans and can be divided into two main complexes: PRC1 and PRC2 (Polycomb repressive complex 1 and 2). Both complexes have a histone modifying activity: PRC1 catalyses the mono-ubiquitination of the lysine 118 on histone H2A (H2AK118Ub) and PRC2 catalyses the tri-methylation of the lysine 27 on histone H3 (H3K27me3).In Drosophila, these complexes are recruited to cis regulatory elements named Polycomb Responsive Elements (PREs) that drive the epigenetic inheritance of silent chromatin states throughout development. Importantly, PcG complexes do not contain DNA-binding activity but are recruited to PREs via their interaction with Transcription Factors (TF) recognizing DNA motifs clustered at PREs. However the mechanism how PREs target PcG complexes is still not well understood due to the complexity of PcG recruitment, which is reflected at different levels: The DNA signature between PREs can differ significantly and several TF are implicated in PcG recruitment, but none of them is sufficient to recruit PcG complexes to PREs. Moreover PcG complexes can cooperate in different ways to stabilize each other’s binding. Finally, another layer of complexity is found at a more global level since PcG complexes do not only bind repressed sites, but they are also found at active regions.Therefore, our working hypothesis is that different classes of PREs exist in Drosophila. My PhD work was thus to define these different classes of PREs on a genome-wide scale and to functionally characterize them in order to get a complete molecular description of PRE function. Understanding how PcG complexes are recruited is of high importance, since deregulation of both, PcG complexes and their recruiting factors can led to cancer and diseases. My work led to the identification of six different classes of PREs that are characterized by different chromatin and genomic features. Interestingly the majority of PREs are associated with active genes that can be divided into housekeeping regulatory regions and developmental enhancers. In addition another class comprises bona fide chromatin domain boundaries. On the other hand PREs associated with repressed chromatin states shows features of previously described PREs and associate with repressed genes and PcG-associated histone marks. Finally another class comprises PREs that are likely in a poised chromatin state. We further demonstrated that PREs located at repressed and active regions differ in their combination of TF. In vivo analyses along with a transcriptomic analysis performed in cell lines mutated for a member of PcG complexes revealed that PcG complexes play a repressive role at both, active and repressed PREs.Taken together, our result suggest an unexpected heterogeneity of PREs and contributes to the better understanding of their characteristics and function.
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Marianne Entrevan. Caractérisation de la diversité des sites de fixation des protéines du groupe Polycomb chez la Drosophile. Génétique. Université Montpellier, 2017. Français. ⟨NNT : 2017MONTT029⟩. ⟨tel-01972575⟩

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