Primers used in ChIP-qPCR.

Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, for the first time in Plasmodium: it was found in two human malaria parasites, P. falciparum and P. knowlesi, and also in vivo in two rodent malaria models, P. yoelii and P. berghei. Histones were increasingly lactylated in response to elevated lactate levels in vitro and in vivo, making this mark uniquely well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia in the human host. Mass spectrometry showed that lysines on several parasite histones could be lactylated, as well as many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible in P. knowlesi than P. falciparum, suggesting that P. falciparum may have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent model P. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic ‘dormancy’.表观遗传过程在恶性疟原虫（Plasmodium falciparum）的生物学功能中发挥重要作用。本研究首次在疟原虫中鉴定出一种新型表观遗传标记——组蛋白乳酸化修饰（histone lactylation）：该修饰在两种人体疟原虫（恶性疟原虫P. falciparum与诺氏疟原虫P. knowlesi）以及两种啮齿类疟疾模型虫株（约氏疟原虫P. yoelii与伯氏疟原虫P. berghei）中均被检测到。无论在体外还是体内环境中，组蛋白乳酸化水平均随乳酸盐浓度升高而逐步上调，这使得该标记具备作为代谢传感器的独特优势——因为重症恶性疟疾通常会导致人类宿主出现高乳酸血症（hyperlactataemia）。质谱分析结果显示，疟原虫的多种组蛋白赖氨酸残基以及大量非组蛋白染色质蛋白均可发生乳酸化修饰。相较于恶性疟原虫，诺氏疟原虫的组蛋白乳酸化修饰丰度更低、诱导性更弱，这提示恶性疟原虫或许已演化出针对其致病特征的特异性表观遗传调控机制。最后，在约氏疟原虫啮齿类感染模型中，高乳酸血症与疟原虫的转录组程序呈显著相关，该程序提示寄生虫处于代谢“休眠”状态。