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Sara El Kennani

Translational epigenetics applied to histone variants and chromatin readers

Published on 12 December 2019
Thesis presented December 12, 2019

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 hazardous, complicating their identification by mass spectrometry. Thus, I developed a comprehensive database, called MS_HistoneDB, dedicated to the detection of histone variants from murine and human samples by mass spectrometry. Also, the use of immunological tests makes it difficult to discriminate at the protein level of 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). 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.

Keywords:
Chromatin, histone variants, targeted proteomics, Candida spp., BET proteins

On-line thesis.