Histone acetyltransferase inhibitor anacardic acid causes changes in global gene expression during in vitro Plasmodium falciparum development.
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 approximately 30 microM. Treatment of the parasites with 20 microM 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 (approximately 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.
Cui
Long
L
Department of Entomology, The Pennsylvania State University, 501 ASI Building, University Park, PA 16802, USA.
Miao
Jun
J
Furuya
Tetsuya
T
Fan
Qi
Q
Li
Xinyi
X
Rathod
Pradipsinh K
PK
Su
Xin-Zhuan
XZ
Cui
Liwang
L
D048729:Anacardic Acids / Q000494:pharmacology*; D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048729:Anacardic Acids; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C088115:anacardic acid; D051548:Histone Acetyltransferases