Histone acetyltransferase inhibitor anacardic acid causes changes in global gene expression during in vitro Plasmodium falciparum development

Long Cui, Jun Miao, Tetsuya Furuya, Qi Fan, Xinyi Li, Pradipsinh K. Rathod, Xin Zhuan Su, Liwang Cui

Research output: Contribution to journalArticle

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Abstract

To better understand the role of histone lysine acetylation in transcription in Plasmodium falciparum, we sought to attenuate histone acetyltransferase (HAT) activity using anacardic acid (AA). We showed that AA reversibly and noncompetitively inhibited the HAT activity of recombinant PfGCN5. To a lesser extent, AA inhibited the PfGCN5 activity in parasite nuclear extracts but did not affect histone deacetylase activity. AA blocked the growth of both chloroquine-sensitive and -resistant strains, with a 50% inhibitory concentration of ∼30 μM. Treatment of the parasites with 20 μM of AA for 12 h had no obvious effect on parasite growth or gross morphology but induced hypoacetylation of histone H3 at K9 and K14, but not H4 at K5, K8, K12, and K16, suggesting inhibition of the PfGCN5 HAT. Microarray analysis showed that this AA treatment resulted in twofold or greater change in the expression of 271 (∼5%) parasite genes in late trophozoites, among which 207 genes were downregulated. Cluster analysis of gene expression indicated that AA mostly downregulated active genes, and this gene pool significantly overlapped with that enriched for H3K9 acetylation. We further demonstrated by chromatin immunoprecipitation and real-time PCR that AA treatment reduced acetylation near the putative promoters of a set of downregulated genes. This study suggests that the parasiticidal effect of AA is at least partially associated with its inhibition of PfGCN5 HAT, resulting in the disturbance of the transcription program in the parasites.

Original languageEnglish (US)
Pages (from-to)1200-1210
Number of pages11
JournalEukaryotic Cell
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2008

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Histone Acetyltransferases
Plasmodium falciparum
Gene Expression
Parasites
Acetylation
Down-Regulation
Histones
Genes
In Vitro Techniques
anacardic acid
Gene Pool
Trophozoites
Histone Deacetylases
Chromatin Immunoprecipitation
Chloroquine
Microarray Analysis
Growth
Inhibitory Concentration 50
Lysine
Cluster Analysis

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

Cui, Long ; Miao, Jun ; Furuya, Tetsuya ; Fan, Qi ; Li, Xinyi ; Rathod, Pradipsinh K. ; Su, Xin Zhuan ; Cui, Liwang. / Histone acetyltransferase inhibitor anacardic acid causes changes in global gene expression during in vitro Plasmodium falciparum development. In: Eukaryotic Cell. 2008 ; Vol. 7, No. 7. pp. 1200-1210.
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Histone acetyltransferase inhibitor anacardic acid causes changes in global gene expression during in vitro Plasmodium falciparum development. / Cui, Long; Miao, Jun; Furuya, Tetsuya; Fan, Qi; Li, Xinyi; Rathod, Pradipsinh K.; Su, Xin Zhuan; Cui, Liwang.

In: Eukaryotic Cell, Vol. 7, No. 7, 01.07.2008, p. 1200-1210.

Research output: Contribution to journalArticle

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AU - Cui, Long

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