The malaria parasite Plasmodium falciparum has an unusually euchromatic genome with poorly conserved positioning of nucleosomes in intergenic sequences and poorly understood mechanisms of gene regulation. Variant histones and histone modifications determine nucleosome stability and recruit trans factors, but their combinatorial contribution to gene regulation is unclear. Here, we show that the histone H3 acetylations H3K18ac and H3K27ac and the variant histone Pf H2A.Z are enriched together at regulatory sites upstream of genes. H3K18ac and H3K27ac together dynamically mark regulatory regions of genes expressed during the asexual life cycle. In contrast, H3K4me1 is depleted in intergenic sequence and dynamically depleted upstream of expressed genes. The temporal pattern of H3K27ac and H3K18ac enrichment indicates that they accumulate during S phase and mitosis and are retained at regulatory sequences until at least G1 phase and after cessation of expression of the cognate genes. We integrated our ChIPseq data with existing datasets to show that in schizont stages H3K18ac, H3K27ac and Pf H2A.Z colocalise with the transcription factor PfAP2-I and the bromodomain protein PfBDP1 and are enriched at stably positioned nucleosomes within regions of exposed DNA at active transcriptional start sites. Using transient transfections we showed that sequences enriched with colocalised H3K18ac, H3K27ac and Pf H2A.Z possess promoter activity in schizont stages, but no enhancer-like activity. The dynamic H3 acetylations define P. falciparum regulatory sequences and contribute to gene activation. These findings expand the knowledge of the chromatin landscape that regulates gene expression in P. falciparum.

中文翻译：

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与基因表达和基因组可及性相关的组蛋白修饰在恶性疟原虫调节序列中得到了动态富集

疟疾疟原虫恶性疟原虫具有异常的常染色体基因组，其核小体在基因间序列中的保守性定位较差，并且对基因调控的机理了解甚少。变异的组蛋白和组蛋白修饰决定了核小体的稳定性并募集了反式因子，但是它们对基因调控的组合作用尚不清楚。在这里，我们显示了组蛋白H3乙酰化H3K18ac和H3K27ac和变异组蛋白Pf H2A.Z在基因上游的调控位点富集在一起。H3K18ac和H3K27ac一起动态标记了无性生活周期中表达的基因的调控区域。相反，H3K4me1在基因间序列中被耗尽，而在表达基因的上游被动态地耗尽。H3K27ac和H3K18ac富集的时间模式表明，它们在S期和有丝分裂期间积累，并保留在调节序列上，直到至少G1期以及相关基因的表达停止。我们将ChIPseq数据与现有数据集进行了整合，显示在裂殖体阶段H3K18ac，H3K27ac和Pf H2A.Z与转录因子PfAP2-I和溴结构域蛋白PfBDP1共同定位，并在活跃转录时在暴露的DNA区域内稳定定位的核小体上富集。启动站点。使用瞬时转染，我们显示富含共定位的H3K18ac，H3K27ac和Pf H2A.Z的序列在裂殖体阶段具有启动子活性，但没有增强子样活性。动态的H3乙酰化作用可定义恶性疟原虫的调控序列，并有助于基因激活。