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Theses

Investigation translationnelle de la chromatine

Abstract : DNA is organized via histones, the leading players in the compaction of genetic material. Technological evolution has favored the discovery of many protein variants. However, the annotation of the latter was unconventional, complicating their identification by mass spectrometry. Thus, I developed a comprehensive database, called MS_HistoneDB, dedicated to the detection of histone variants by mass spectrometry. MS_HistoneDB allows the use of murine and human samples. Also, the use of immunological tests makes it difficult to discriminate at the protein level of almost similar variants. Thus, I developed a targeted mass spectrometry analysis method to detect and quantify histone variants in a multiplex assay. This methodology has been applied in the investigation of chromatin during spermatogenesis, in mouse models, physiological or pathological mimicking male infertility.Another aspect of my work focused on proteins that bind modified forms of histones. Thus, I studied the "readers" of the BET family (Bromodomain and Extra-terminal domain). These proteins are recruited on chromatin via their bromodomains, a specific module recognizing acetylated histones. Their extra-terminal domain acts as a recruitment platform for transcriptional regulators. These proteins are conserved in the yeast Saccharomyces cerevisiae, and also in fungal pathogens responsible for invasive infections, where the only member is called Bdf1. Thus, I studied the extra-terminal domain of Bdf1 and demonstrated that it is essential for yeast survival. Then, I explored the molecular mechanisms involved. Finally, selective inhibitors are being developed in pathogenic yeast species. All of this work paves the way for the development of a new therapeutic class of antifungals.
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https://tel.archives-ouvertes.fr/tel-03270933
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Submitted on : Friday, June 25, 2021 - 11:16:19 AM
Last modification on : Tuesday, March 29, 2022 - 3:10:41 AM
Long-term archiving on: : Sunday, September 26, 2021 - 9:24:40 PM

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Sara El Kennani. Investigation translationnelle de la chromatine. Biotechnologies. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV059⟩. ⟨tel-03270933⟩

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