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首页> 外文期刊>Epigenetics & Chromatin >Histone 4 lysine 8 acetylation regulates proliferation and host–pathogen interaction in Plasmodium falciparum
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Histone 4 lysine 8 acetylation regulates proliferation and host–pathogen interaction in Plasmodium falciparum

机译：组蛋白4赖氨酸8乙酰化调节恶性疟原虫的增殖和宿主-病原体相互作用

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Background The dynamics of histone modifications in Plasmodium falciparum indicates the existence of unique mechanisms that link epigenetic factors with transcription. Here, we studied the impact of acetylated histone code on transcriptional regulation during the intraerythrocytic developmental cycle (IDC) of P. falciparum . Results Using a dominant-negative transgenic approach, we showed that acetylations of histone H4 play a direct role in transcription. Specifically, these histone modifications mediate an inverse transcriptional relationship between the factors of cell proliferation and host–parasite interaction. Out of the four H4 acetylations, H4K8ac is likely the rate-limiting, regulatory step, which modulates the overall dynamics of H4 posttranslational modifications. H4K8ac exhibits maximum responsiveness to HDAC inhibitors and has a highly dynamic distribution pattern along the genome of P. falciparum during the IDC. Moreover, H4K8ac functions mainly in the euchromatin where its occupancy shifts from intergenic regions located upstream of 5′ end of open reading frame into the protein coding regions. This shift is directly or indirectly associated with transcriptional activities at the corresponding genes. H4K8ac is also active in the heterochromatin where it stimulates expression of the main antigenic gene family ( var ) by its presence in the promoter region. Conclusions Overall, we demonstrate that H4K8ac is a potential major regulator of chromatin-linked transcriptional changes during P. falciparum life cycle which is associated not only with euchromatin but also with heterochromatin environment. This is potentially a highly significant finding that suggests a regulatory connection between growth and parasite–host interaction both of which play a major role in malaria parasite virulence.
机译：背景恶性疟原虫中组蛋白修饰的动力学表明存在将表观遗传因子与转录联系起来的独特机制。在这里，我们研究了恶性疟原虫的红细胞内发育周期（IDC）期间乙酰化组蛋白密码对转录调控的影响。结果使用显性阴性转基因方法，我们表明组蛋白H4的乙酰化在转录中起直接作用。具体来说，这些组蛋白修饰介导细胞增殖与宿主-寄生虫相互作用的因子之间的逆转录关系。在四种H4乙酰化中，H4K8ac可能是限速的调节步骤，它调节H4翻译后修饰的整体动力学。 H4K8ac对HDAC抑制剂表现出最大的响应能力，并且在IDC期间沿恶性疟原虫的基因组具有高度动态的分布模式。此外，H4K8ac主要在常染色质中起作用，其占有率从开放阅读框5'端上游的基因间区域转移到蛋白质编码区域。这种转变与相应基因的转录活性直接或间接相关。 H4K8ac在异染色质中也具有活性，在异染色质中，H4K8ac通过在启动子区域中的存在而刺激主要抗原基因家族（var）的表达。结论总体而言，我们证明H4K8ac是恶性疟原虫生命周期中与染色质相关的转录变化的潜在主要调控因子，不仅与常染色质有关，而且与异染色质环境有关。这可能是一个非常重要的发现，表明生长与寄生虫-宿主相互作用之间存在调节联系，两者在疟疾寄生虫毒力中均起主要作用。

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