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Etude de l'influence de la méthylation des histones sur la structure chromatinienne et l'expression génique chez Toxoplasma gondii.

Abstract : Toxoplasma gondii in an intracellular parasite that belongs Apicomplexa phylum. This pathogen is responsible for toxoplasmosis. This opportunistic parasite causes cerebral toxoplasmosis in immunodepressed individuals and the fœtus. Interconversion from the virulent tachyzoïte form of the parasite to its quiescent bradyzoïte form is a critical point in the pathogenesis. This process involves a tiny regulation of the gene expression. Previous studies suggest a transcriptional control of interconversion, including a stage specific expression of genes. However, this parasite and the whole phylum Apicomplexa are characterized by the presence of few specific transcription factors. We hypothesized that the level of genes expression in Toxoplasma gondii is finely regulated by physical structure and chemical nature of chromatin. When I started my PhD, very few was known about chromatin remodeling in Toxoplasma. Today, our results and others results, lead to the idea of the existence of a highly sophisticated "parasitic histone code”. During my PhD, we first identified and characterized H4K20 methylase of the Set8 family in Toxoplasma gondii. H4K20 methylation is considered to have an evolutionary ancient role in DNA repair/genome integrity, while its function in heterochromatin function/gene expression is thought to have arisen later during evolution. Remarkably, parasite TgSet8-related proteins display H4K20 mono-, di-, and trimethylase activities, whereas HSET8 is monomethylase-restricted. Structurally, few residues forming the substrate-specific channel dictate the enzyme methylation multiplicity. These enzyme and it's mark H4K20-me1 are cell cycle regulated and focally enriched at pericentric and telomeric heterochromatin in T. gondii et P. falciparum. Taken together, our findings show that the heterochromatic function of SET8 and H4K20 is not restricted to metazoans. Secondly, we have investigated the role of KMTox, another histone lysine-methyltransferase, in Toxoplasma gondii. KMTox is a nuclear protein that holds a High Mobility Group domain, which is thought to recognize bent DNA. The enzyme methylates both histones H4 and H2A in vitro with a great preference for the substrate in reduced conditions. Importantly, KMTox interacts specifically with the typical 2-cys peroxiredoxin-1 and the binding is to some extent enhanced upon oxidation. It appears that the cellular functions that are primarily regulated by the KMTox are antioxidant response and maintenance of cellular homeostasis. KMTox may regulate gene expression in T. gondii by providing the rapid re-arrangement of chromatin domains and by interacting with the redox-sensor TgPrx1 contribute to establish the antioxidant response in T. gondi.
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https://tel.archives-ouvertes.fr/tel-00340435
Contributor : Céline Sautel <>
Submitted on : Thursday, November 20, 2008 - 7:01:09 PM
Last modification on : Friday, November 6, 2020 - 4:04:17 AM
Long-term archiving on: : Tuesday, September 18, 2012 - 12:30:33 PM

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  • HAL Id : tel-00340435, version 1

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Céline Sautel. Etude de l'influence de la méthylation des histones sur la structure chromatinienne et l'expression génique chez Toxoplasma gondii.. Biochimie [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2008. Français. ⟨tel-00340435⟩

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