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Etude du réseau transcriptionnel du gène Xist, acteur principal de l'inactivation du chromosome X

Abstract : X-chromosome inactivation is evolution's answer to compensate for the gonosomal discrepancy between male (XY) and female (XX). This phenomenon therefore serves to put both sexes on an equal footing by limiting the amount of transcripts produced from the X chromosomes in female cells. During my Ph.D., I tried to contribute to the study of transcriptional regulatory mechanisms, including activation of the two main players in inactivation: Xist (for X-inactive Specific transcript) and Tsix, its antisense transcript. Both genes produce non-coding transcripts essential for correct initiation of this epigenetic phenomenon. Xist RNA coats one of the two X chromosomes in female cells to induce inactivation, and does so in a manner very related to the early embryo development. During these four years, I began to map the binding of several proteins along the Xist/Tsix locus in order to obtain a better understanding of the mechanisms leading to Xist overexpression following the disappearance of its repressors during differentiation. This mapping has been performed in several wild-type or mutant mouse embryonic stem cell strains (which are capable of summarizing XCI ex vivo). I was able to establish a model for transcriptional regulation of the non-coding Xist RNA, involving several proteins known for their role in transcriptional regulation (CTCF and YY1) as well as in the formation of three-dimensional structures (cohesin). The relevance of this model is reinforced by our studies showing that many aspects of this model are conserved throughout evolution (including humans). I have also contributed to the discovery of new Tsix activators, some pluripotency factors binding to the DxPas34 minisatellite to regulate the antisense's transcription elongation. These results thus provide important information about the mechanisms regulating Xchromosome inactivation during early development of the embryo.
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Submitted on : Thursday, April 18, 2013 - 10:56:09 AM
Last modification on : Tuesday, December 8, 2020 - 3:34:43 AM
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  • HAL Id : tel-00815096, version 1


Andrew Oldfield. Etude du réseau transcriptionnel du gène Xist, acteur principal de l'inactivation du chromosome X. Génétique humaine. Université Pierre et Marie Curie - Paris VI, 2010. Français. ⟨NNT : 2010PA066319⟩. ⟨tel-00815096⟩



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