<i>Toxoplasma gondii</i>gene expression is under the control of regulatory pathways acting through chromatin structure

Bougdour, Alexandre; Sautel, Céline F; Cannella, Dominique; Braun, Laurence; Hakimi, Mohamed‐Ali

doi:10.1051/parasite/2008153206

Cited by 6 publications

(7 citation statements)

References 18 publications

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“…Collectively, these estimates suggest that the phenotypic differences between type I strains are unlikely to be due to sequence differences (i.e., mutations) but more likely stem from epigenetic differences in gene expression. Recent studies have emphasized the relative importance of epigenetic factors in controlling gene expression in T. gondii (5,16). This suggests that a great deal of phenotypic variation might be expected based on passage history or other environmental influences.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

et al. 2009

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Toxoplasma gondii has an unusual population structure consisting of three clonal lineages that predominate in North America and Europe. This simple pattern has encouraged the use of only a few laboratory isolates that are representative of each lineage. Principle among these is the type I RH strain, originally isolated from a child with encephalitis some 70 years ago. Comparison of different passages of the RH strain that have been propagated differently over the intervening time period revealed that the commonly used clonal line called RH-ERP was not representative of natural isolates of the type I lineage. Notably, RH-ERP formed much larger plaques than other type 1 strains, including a separate, earlier derived isolate of the RH strain. The RH-ERP variant also showed enhanced extracellular survival, faster growth, and decreased differentiation compared to the prototype type I strain GT1. Comparison of gene expression differences in the RH-ERP line revealed that several ABC transporters were upregulated, which may provide a growth advantage in vitro. These findings illustrate that dramatic phenotypic changes can arise in laboratory strains, emphasizing the need for comparison with recent clinical isolates.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

et al. 2009

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Section: Interfering With the Epigenome To Understand Gene Expressionmentioning

confidence: 99%

“…, 2008). We showed that specific inhibition of TgHDAC3 by the cyclopeptide FR235222 disrupts the steady‐state level of histone H4 acetylation across the genome inducing derepression of stage‐specific genes (Bougdour et al. , 2008).…”

Section: Interfering With the Epigenome To Understand Gene Expressionmentioning

confidence: 99%

“…To understand the regulation of gene expression in T. gondii, we and others took advantage of HDAC inhibitors that alter the writing of the histone code and thereby gene transcription (Boyle et al, 2006;Bougdour et al, 2008). We showed that specific inhibition of TgHDAC3 by the cyclopeptide FR235222 disrupts the steady-state level of histone H4 acetylation across the genome inducing derepression of stage-specific genes (Bougdour et al, 2008). In the same study, we isolated parasite lines resistant to the molecule; single-point mutations found in mutagenized parasites target the amino acid T99 in TgHDAC3.…”

Section: Interfering With the Epigenome To Understand Gene Expressionmentioning

confidence: 99%

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Chromatin modifications: implications in the regulation of gene expression inToxoplasma gondii

Bougdour

Braun

Cannella

et al. 2010

Cellular Microbiology

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SummaryThe apicomplexan Toxoplasma gondii completes its life cycle by successive processes of parasite differentiation that rely on a tight control of gene expression to ensure appropriate protein profiles on time. During the last 5 years, several groups have pioneered this field of investigation, suggesting that epigenetics could play an important role in the control of parasite gene expression. Histone modifications serve as an effective way to regulate gene transcription but they do not operate alone; rather, they act in concert with other putative epigenetic information carriers (histone variants, small RNAs) and DNA sequence-specific transcription factors to modulate the higher-order structure of the chromatin fibre and govern the on-time recruitment of the transcriptional machinery to specific genes. Regarding the 'histone code' hypothesis, the parasite is endowed with a rich repertoire of histone-modifying enzymes catalysing site-selective modifications, which are subsequently interpreted by effector proteins that recognize specific covalent marks. Still, several peculiarities seem unique to T. gondii. This review is a synthesis of the current knowledge of how epigenetics contribute to the control of gene expression in T. gondii and, likely, other Apicomplexa.

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“…This observation is intriguing in light of the complex life cycle of the parasite, which inevitably requires tight gene regulation. Despite the paucity of recognizable TFs, apicomplexa are endowed with a rich repertoire of enzymes associated with epigenetics and chromatin remodeling, and this observation has fueled the idea that epigenetics could play an important role in the control of gene expression (7,17,34). Therefore, chromatin regulators make suitable targets for the development of therapeutics.…”

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confidence: 99%

Activity of the Histone Deacetylase Inhibitor FR235222 on Toxoplasma gondii : Inhibition of Stage Conversion of the Parasite Cyst Form and Study of New Derivative Compounds

Maubon

Bougdour

Wong

et al. 2010

Antimicrob Agents Chemother

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Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compound is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compound is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compound impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 derivative compounds. We identified two new molecules that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivatives as new lead compounds in the range of therapeutics available for acute and chronic toxoplasmosis.Toxoplasma gondii is the causative agent of toxoplasmosis and is considered one of the most common parasitic diseases, given its worldwide distribution and its broad range of intermediate hosts (18). T. gondii is an intracellular parasite that belongs to the Apicomplexa family, like Plasmodium species, with which it shares major biologic and genetic similarities (4,35). Its life cycle is complex and is characterized by the interconversion phenomenon, which is the ability of the parasite to differentiate from a tachyzoite form to a cystic structure (containing the bradyzoite form) and vice versa. Cysts, which are responsible for the chronic form of toxoplasmosis, are believed to not cause symptoms in healthy people, but if they are reactivated, they can be potentially life-threatening in immunocompromised patients. Treatments of acute toxoplasmosis are currently based on the combination of pyrimethamine (PYR) and sulfadiazine, which can be associated with cytopenia and allergic skin reactions, respectively, as possible side effects. The antibiotics cotrimoxazole and clindamycin have been used as second-line treatments (14). In addition, medicines used so far in the clinical setting target the tachyzoite form, while the tissue cysts remain unaffected. Despite the highly active research on this parasite and the description of dozens of potential new molecular targets, no candidates presenting an anticystic activity have been identified, therefore providing no grounds for a treatment able to eliminate T. gondii from infected patients. Discovering...

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Toxoplasma gondiigene expression is under the control of regulatory pathways acting through chromatin structure

Cited by 6 publications

References 18 publications

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

Chromatin modifications: implications in the regulation of gene expression inToxoplasma gondii

Activity of the Histone Deacetylase Inhibitor FR235222 on Toxoplasma gondii : Inhibition of Stage Conversion of the Parasite Cyst Form and Study of New Derivative Compounds

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