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Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites
- Source :
- Journal of Experimental Medicine, Journal of Experimental Medicine, Rockefeller University Press, 2009, 206 (4), pp.953-66. ⟨10.1084/jem.20082826⟩, The Journal of Experimental Medicine, The Journal of Experimental Medecine, The Journal of Experimental Medecine, The Rockefeller University Press, 2009, 206 (4), pp.953-66. ⟨10.1084/jem.20082826⟩, Journal of Experimental Medicine, 2009, 206 (4), pp.953-66. ⟨10.1084/jem.20082826⟩
- Publication Year :
- 2009
- Publisher :
- Rockefeller University Press, 2009.
-
Abstract
- International audience; Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although little is yet known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. We investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase inhibitor (HDACi). We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi's such as trichostatin A and the clinically relevant compound pyrimethamine. We identify T. gondii HDAC3 (TgHDAC3) as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (nonreplicative) stage. Additionally, via its anti-TgHDAC3 activity, FR235222 influences the expression of approximately 370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDACi of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and, likely, other Apicomplexa.
- Subjects :
- MESH: Cell Differentiation
Plasmodium
medicine.drug_class
Cellular differentiation
MESH: Apicomplexa
Immunology
Peptides, Cyclic
Article
Histone Deacetylases
Apicomplexa
03 medical and health sciences
parasitic diseases
medicine
Animals
Immunology and Allergy
MESH: Animals
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Epigenetics
Conserved Sequence
MESH: Peptides, Cyclic
030304 developmental biology
Regulation of gene expression
Genetics
Cyclic
0303 health sciences
MESH: Conserved Sequence
biology
MESH: Plasmodium
030306 microbiology
MESH: Toxoplasma
Histone deacetylase inhibitor
Cell Differentiation
biology.organism_classification
MESH: Gene Expression Regulation
3. Good health
Cell biology
Histone Deacetylase Inhibitors
MESH: Histone Deacetylases
Trichostatin A
Histone
Gene Expression Regulation
biology.protein
Protozoa
Peptides
Toxoplasma
medicine.drug
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 206
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....b3a73799fdb453b4ab0fc6aaa73e570e