Histone deacetylases play a major role in the transcriptional regulation of the Plasmodium falciparum life cycle.
Histone deacetylases play a major role in the transcriptional regulation of the Plasmodium falciparum life cycle.
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DOI：
10.1371/journal.ppat.1000737
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发表时间：
2010-01-22
期刊：
影响因子：
6.7
通讯作者：
Bozdech Z
中科院分区：
文献类型：
--
作者：
Chaal BK;Gupta AP;Wastuwidyaningtyas BD;Luah YH;Bozdech Z
疟原虫基因组中转录调控分子因子的明显缺乏，引起了许多关于这些疟原虫生命周期调控机制的问题。表观遗传调控在疟原虫生命周期中的阶段特异性基因表达中起重要作用。为了解决这些问题中的一些，我们分析了全球恶性疟原虫的转录反应，一个有效的抑制剂组蛋白去乙酰化酶的活动（HDAC）。抑制剂apicidin在恶性疟原虫红细胞内发育周期（IDC）的多个阶段诱导了深刻的转录变化，其特征在于大部分基因组的快速激活和抑制。这种反应的一个主要组成部分是诱导基因，否则在IDC的特定阶段或特定的红细胞外阶段抑制。在前体阶段，apicidin诱导组蛋白赖氨酸残基H3K9、H4K8和四乙酰基H4（H4Ac4）的超乙酰化和H3K4me3的去甲基化。有趣的是，我们观察到H4K8Ac和H3K4me3之间以及H3K9Ac和H4Ac4之间的染色体分布的重叠模式。在apicidin诱导的基因表达和组蛋白修饰之间存在显著但部分的关联，其中包括一些阶段特异性转录因子。总之，HDAC活性的抑制导致IDC转录级联的显著失调，这是组蛋白修饰的破坏和阶段特异性转录因子的上调的结果。这些发现表明组蛋白修饰和染色质重塑在疟原虫生命周期的转录调控中起重要作用。这也强调了恶性疟原虫HDAC作为疟疾化疗药物靶标的潜力。 恶性疟原虫是一种寄生性原生动物，是人类疟疾中最致命的一种，每年造成200多万人死亡。它有一个复杂的生命周期，涉及不同的形态阶段，伴随着阶段特异性基因表达在蚊子和人类宿主。疟疾疫苗的缺乏和广泛的耐药性突出了针对不同寄生虫靶标的新型抗疟疾药物的紧迫性。我们发现，组蛋白脱乙酰酶活性的抑制导致恶性疟原虫无性生命周期的多个阶段中转录调控基因的激活和抑制。我们还表明，抑制破坏组蛋白乙酰化和甲基化的稳态水平在恶性疟原虫基因组。我们的数据强烈暗示，在恶性疟原虫中，组蛋白去乙酰化酶活性的抑制导致组蛋白的整体乙酰化显著增加，随后破坏阶段特异性基因表达。这个过程然后导致恶性疟原虫的转录级联的崩溃。因此，组蛋白去乙酰化酶在疟原虫中的重要作用表明其作为疟疾干预策略的分子靶点的高潜力。
The apparent paucity of molecular factors of transcriptional control in the genomes of Plasmodium parasites raises many questions about the mechanisms of life cycle regulation in these malaria parasites. Epigenetic regulation has been suggested to play a major role in the stage specific gene expression during the Plasmodium life cycle. To address some of these questions, we analyzed global transcriptional responses of Plasmodium falciparum to a potent inhibitor of histone deacetylase activities (HDAC). The inhibitor apicidin induced profound transcriptional changes in multiple stages of the P. falciparum intraerythrocytic developmental cycle (IDC) that were characterized by rapid activation and repression of a large percentage of the genome. A major component of this response was induction of genes that are otherwise suppressed during that particular stage of the IDC or specific for the exo-erythrocytic stages. In the schizont stage, apicidin induced hyperacetylation of histone lysine residues H3K9, H4K8 and the tetra-acetyl H4 (H4Ac4) and demethylation of H3K4me3. Interestingly, we observed overlapping patterns of chromosomal distributions between H4K8Ac and H3K4me3 and between H3K9Ac and H4Ac4. There was a significant but partial association between the apicidin-induced gene expression and histone modifications, which included a number of stage specific transcription factors. Taken together, inhibition of HDAC activities leads to dramatic de-regulation of the IDC transcriptional cascade, which is a result of both disruption of histone modifications and up-regulation of stage specific transcription factors. These findings suggest an important role of histone modification and chromatin remodeling in transcriptional regulation of the Plasmodium life cycle. This also emphasizes the potential of P. falciparum HDACs as drug targets for malaria chemotherapy. Plasmodium falciparum, a parasitic protozoan, causes the most lethal form of human malaria, killing more than 2 million people per year. It has a complex life cycle that involves distinct morphological stages accompanied by stage specific gene expression in both the mosquito and human hosts. The lack of a vaccine for malaria and widespread resistance highlights the urgency for new anti-malarial drugs that act on different parasite targets. We show that inhibition of histone deacetylase activities results in activation and repression of transcriptionally regulated genes in multiple stages of the P. falciparum asexual life cycle. We also show that inhibition disrupts the steady-state level of histone acetylation and methylation across the P. falciparum genome. Our data strongly implies that in P. falciparum, inhibition of histone deacetylase activity leads to a dramatic increase in global acetylation of histones and subsequently disruption of stage specific gene expression. This process then leads to a collapse of the transcriptional cascade of P. falciparum. Therefore, the essential role of histone deacetylases in Plasmodium parasites suggests their high potential as molecular targets for malaria intervention strategies.
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