Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites

Bougdour, Alexandre; Maubon, Danièle; Baldacci, Patricia; Ortet, Philippe; Bastien, Olivier; Bouillon, Anthony; Barale, Jean-Christophe; Pelloux, Hervé; Ménard, Robert; Hakimi, Mohamed‐Ali

doi:10.1084/jem.20082826

Cited by 156 publications

(184 citation statements)

References 43 publications

(60 reference statements)

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“…We may be able to add infections caused by protozoan parasites to this list, as genetic studies have shown that most parasite bromodomain proteins are crucial for viability and virulence. Some studies have already begun to examine the effects of bromodomain inhibitors against these protozoan parasites, and these complement previous work showing the antiparasitic activities of KAT and KDAC inhibitors (55)(56)(57)(58)(59)(60)(61)(62)(63).…”

Section: Bromodomain Inhibition In Protozoan Parasitessupporting

confidence: 52%

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Jeffers

Yang

Huang

et al. 2017

Microbiol Mol Biol Rev

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SUMMARY Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As “readers” of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.

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Section: Bromodomain Inhibition In Protozoan Parasitessupporting

confidence: 52%

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Jeffers

Yang

Huang

et al. 2017

Microbiol Mol Biol Rev

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“…The HDAC inhibitor apicidin, which may affect both class I and II HDACs in the parasite, causes profound transcription changes in the parasite, and deregulation of transcription is evident at as early as 1 h posttreatment (18). Similar to the observation with the more specific HDAC inhibitor FR235222 in T. gondii (11), apicidin induces expression of stage-specific genes that are otherwise suppressed during that particular stage of the intraerythrocytic development cycle (IDC) in P. falciparum. Two class III enzymes, PfSir2A (PF13_0152) and PfSir2B (PF14_0489), also named sirtuins, have received considerable attention because of their roles in regulating the mutually exclusive expression of var genes.…”

Section: Chromatin Modifications: Deposition Recognition and Functionsmentioning

confidence: 82%

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

2010

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Malaria is a major public health problem in many developing countries, with the malignant tertian parasite Plasmodium falciparum causing the most malaria-associated mortality. Extensive research, especially with the advancement of genomics and transfection tools, has highlighted the fundamental importance of chromatinmediated gene regulation in the developmental program of this early-branching eukaryote. The Plasmodium parasite genomes reveal the existence of both canonical and variant histones that make up the nucleosomes, as well as a full collection of conserved enzymes for chromatin remodeling and histone posttranslational modifications (PTMs). Recent studies have identified a wide array of both conserved and novel histone PTMs in P. falciparum, indicating the presence of a complex and divergent "histone code." Genome-wide analysis has begun to decipher the nucleosome landscape and histone modifications associated with the dynamic organization of chromatin structures during the parasite's life cycle. Focused studies on malaria-specific phenomena such as antigenic variation and red cell invasion pathways shed further light on the involvement of epigenetic mechanisms in these processes. Here we review our current understanding of chromatin-mediated gene regulation in malaria parasites, with specific reference to exemplar studies on antigenic variation and host cell invasion.Malaria continues to be a major cause of mortality and morbidity in tropical countries, bringing a death toll of ϳ1 million each year. Four human parasites (Plasmodium falciparum, P. vivax, P. malariae, and P. ovale) and a monkey parasite (P. knowlesi) have been found to infect humans naturally. P. falciparum causes the malignant form of malaria and is responsible for most malaria-associated human deaths. Intensified research in the past decade has greatly improved our understanding of the parasites and the disease they cause, especially with the sequencing of multiple parasite genomes. A striking finding from global microarray analyses of parasite gene expression is the tightly regulated transcription program during the parasite's life cycle, with genes expressed in a "just-in-time" manner (12, 93). Bioinformatic analysis has recognized a general conservation of the basal transcription machinery (15), but the scarcity of recognizable specific transcription factors in the parasite genome has led to speculation about the existence of a divergent transcription mechanism used by the malaria parasites (2, 25). However, this speculation may be inaccurate, as recent studies revealed the presence of the AP2 family of transcription factors (4, 35), which have undergone lineagespecific expansion in apicomplexan parasites (75). Nevertheless, the full complement of chromatin-modifying proteins encoded in apicomplexan parasite genomes underlines the significance of epigenetic mechanisms in transcription regulation (2,66,75,140). While epigenetic mechanisms are being intensively studied in model eukaryotes, only recently have they been explored in the m...

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“…Using the intracellular apicomplexan parasite Toxoplasma gondii as a model, we and others have established that histone acetylation is a critical posttranslational modification involved in parasite viability and development (11,36). Lysine acetylation is also a validated drug target in protozoan parasites based on the antiparasite effects of lysine deacetylase (KDAC) inhibitors, such as apicidin and FR235222 (4,9).…”

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confidence: 99%

Lysine Acetylation Is Widespread on Proteins of Diverse Function and Localization in the Protozoan Parasite Toxoplasma gondii

2012

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While histone proteins are the founding members of lysine acetylation substrates, it is now clear that hundreds of other proteins can be acetylated in multiple compartments of the cell. Our knowledge of the scope of this modification throughout the kingdom of life is beginning to emerge, as proteome-wide lysine acetylation has been documented in prokaryotes, Arabidopsis thaliana, Drosophila melanogaster, and human cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify parasite peptides enriched by immunopurification with acetyl-lysine antibody, we produced the first proteome-wide analysis of acetylation for a protozoan organism, the opportunistic apicomplexan parasite Toxoplasma gondii. The results show that lysine acetylation is abundant in the actively proliferating tachyzoite form of the parasite, which causes acute toxoplasmosis. Our approach successfully identified known acetylation marks on Toxoplasma histones and ␣-tubulin and detected over 400 novel acetylation sites on a wide variety of additional proteins, including those with roles in transcription, translation, metabolism, and stress responses. Importantly, an extensive set of parasite-specific proteins, including those found in organelles unique to Apicomplexa, is acetylated in the parasite. Our data provide a wealth of new information that improves our understanding of the evolution of this vital regulatory modification while potentially revealing novel therapeutic avenues. We conclude from this study that lysine acetylation was prevalent in the early stages of eukaryotic cell evolution and occurs on proteins involved in a remarkably diverse array of cellular functions, including those that are specific to parasites. P rotozoan parasites are responsible for significant morbidity and mortality around the world, and new drug targets are sorely needed. Using the intracellular apicomplexan parasite Toxoplasma gondii as a model, we and others have established that histone acetylation is a critical posttranslational modification involved in parasite viability and development (11,36). Lysine acetylation is also a validated drug target in protozoan parasites based on the antiparasite effects of lysine deacetylase (KDAC) inhibitors, such as apicidin and FR235222 (4, 9).Recent studies have demonstrated that lysine acetylation occurs on a multitude of other proteins beyond histones (22, 31). Not only are there nonhistone proteins acetylated in the nucleus, but proteins in the cytoplasm and mitochondria contain acetylated residues as well. The development of specific acetyl-lysine antibodies to enrich acetylated tryptic peptides prior to identification by mass spectrometry has allowed lysine acetylation to be mapped at the whole-proteome level. So-called "acetylomes" have been described for prokaryotes (15,42,50), plants (12, 45), Drosophila melanogaster (43), and human cells (6, 21, 51). Proteins involved in nearly every facet of cell biology, particularly proteins with roles in metabolism, translation, folding, DNA packaging, and ...

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Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites

Cited by 156 publications

References 43 publications

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

Lysine Acetylation Is Widespread on Proteins of Diverse Function and Localization in the Protozoan Parasite Toxoplasma gondii

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