A comprehensive epigenome map of Plasmodium falciparum reveals unique mechanisms of transcriptional regulation and identifies H3K36me2 as a global mark of gene suppression.
A comprehensive epigenome map of Plasmodium falciparum reveals unique mechanisms of transcriptional regulation and identifies H3K36me2 as a global mark of gene suppression.
复制标题
DOI：
10.1186/s13072-015-0029-1
复制
发表时间：
2015
影响因子：
3.9
通讯作者：
Galande S
中科院分区：
文献类型：
--
作者：
Karmodiya K;Pradhan SJ;Joshi B;Jangid R;Reddy PC;Galande S
表观遗传机制在调节恶性疟原虫（疟疾的病原体）复杂生命周期/发病机制中的作用一直知之甚少。为了阐明阶段特异性表观遗传调控，我们对恶性疟原虫的多个组蛋白修饰进行了全基因组定位。为了进一步了解恶性疟原虫及其宿主人类的转录调控差异，我们比较了它们的组蛋白修饰谱。我们的综合比较分析表明，通过平衡基因和差异组蛋白修饰，疟疾寄生虫的转录调节模式不同。此外，组蛋白修饰谱分析预测了562个产生反义rna的基因和335个具有双向启动子活性的基因，这提出了rna介导恶性疟原虫转录调控的有趣可能性。有趣的是，我们发现H3K36me2作为一个全局抑制标记，并且通过激活标记与H3K36me2在恶性疟原虫中的比例微调基因调控。这种新的基因调控机制得到了以下事实的支持：在野生型恶性疟原虫中，敲除SET基因（负责H3K36甲基化）导致H3K36me2占用率最高的基因上调。此外，毒力（var）基因大多是静止的，并由一组独特的激活（H4ac）和抑制（H3K9me3）标记，这些标记与其他疟原虫管家基因是互斥的。我们的研究揭示了恶性疟原虫表观遗传调控的独特可塑性，可以影响寄生虫的毒力和致病性。恶性疟原虫及其宿主组蛋白编码和转录调控的差异将为抗疟原虫表观遗传药物的开发开辟新的途径。本文的在线版本（doi:10.1186/s13072-015-0029-1）包含补充材料，授权用户可以使用。
Role of epigenetic mechanisms towards regulation of the complex life cycle/pathogenesis of Plasmodium falciparum, the causative agent of malaria, has been poorly understood. To elucidate stage-specific epigenetic regulation, we performed genome-wide mapping of multiple histone modifications of P. falciparum. Further to understand the differences in transcription regulation in P. falciparum and its host, human, we compared their histone modification profiles. Our comprehensive comparative analysis suggests distinct mode of transcriptional regulation in malaria parasite by virtue of poised genes and differential histone modifications. Furthermore, analysis of histone modification profiles predicted 562 genes producing anti-sense RNAs and 335 genes having bidirectional promoter activity, which raises the intriguing possibility of RNA-mediated regulation of transcription in P. falciparum. Interestingly, we found that H3K36me2 acts as a global repressive mark and gene regulation is fine tuned by the ratio of activation marks to H3K36me2 in P. falciparum. This novel mechanism of gene regulation is supported by the fact that knockout of SET genes (responsible for H3K36 methylation) leads to up-regulation of genes with highest occupancy of H3K36me2 in wild-type P. falciparum. Moreover, virulence (var) genes are mostly poised and marked by a unique set of activation (H4ac) and repression (H3K9me3) marks, which are mutually exclusive to other Plasmodium housekeeping genes. Our study reveals unique plasticity in the epigenetic regulation in P. falciparum which can influence parasite virulence and pathogenicity. The observed differences in the histone code and transcriptional regulation in P. falciparum and its host will open new avenues for epigenetic drug development against malaria parasite. The online version of this article (doi:10.1186/s13072-015-0029-1) contains supplementary material, which is available to authorized users.