The HAT Inhibitor Anacardic Acid Leads to Changes in Global Gene Expression During in vitro P.falciparum Development

ABSTRACT: To better understand the role of histone lysine acetylation in transcription in Plasmodium falciparum, we sought to attenuate the histone acetyltransferase (HAT) activity of PfGCN5 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 the histone deacetylase activity. AA blocked the growth of both chloroquine-sensitive and -resistant strains with a 50% inhibitory concentration of ~30 uM. Treatment of the parasites with 20 uM 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 of specific inhibition of the PfGCN5 HAT. Microarray analysis showed that this AA treatment disturbed the parasite transcription program, resulting in ≥2-fold change in the expression of 271 (~5%) parasite genes in late trophozoites, among which 207 genes were down-regulated. Interestingly, a significant proportion of the down-regulated genes is potentially associated with signal transduction and transcription. Furthermore, cluster analysis of gene expression indicated that AA mostly down-regulated active genes, and this gene pool significantly overlapped with that enriched for H3K9 acetylation. We further demonstrated by chromatin immunoprecipitation and real-time polymerase chain reaction that AA treatment reduced acetylation near the putative promoters of a set of down-regulated genes. The identification of AA as a PfGCN5 inhibitor offers a useful tool for further functional analysis of epigenetics in transcription regulation in malaria parasites.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE11763 | GEO | 2008/06/13

SECONDARY ACCESSION(S): PRJNA105943

REPOSITORIES: GEO