The function of histone H3 lysine 76 methylation in host-induced differentiation in Trypanosoma brucei

锥虫是一种哺乳动物病原体，寄生在不同宿主中的生活史复杂。基因表达谱的变化导致特定的生命周期阶段，对于适应非常不同的寄主环境至关重要。锥虫主要通过转录后机制调节mRNA水平。然而，越来越多的证据表明，染色质结构的变化与阶段分化过程中差异基因的活性有关。此外，锥虫体组蛋白具有多种翻译后修饰，其中一些参与了其他生物体的转录调控。组蛋白修饰参与分化过程的第一个直接证据是组蛋白甲基转移酶DOT1B的靶向缺失，这导致血流阶段的寄生虫不能分化到飞行中肠期。在这个项目中，我们将研究宿主诱导分化过程中核结构的变化，特别是组蛋白修饰的亚核分布，以及特定修饰对差异调控基因活性状态的分配。我们将验证染色质重塑参与宿主环境触发的基因表达调控的假设。

Trypanosomes are mammalian pathogens with a complex parasitic life cycle in different hosts. Changes in gene expression profiles that result in specialized life cycle stages are crucial to adapt to very different host environments. Trypanosomes mainly regulate mRNA levels by posttranscriptional mechanisms. Nevertheless, there is increasing evidence that changes in chromatin structure are correlated with differential gene activity during stage differentiation. Furthermore, trypanosome histones carry multiple post-translational modifications, some of which are involved in transcriptional regulation in other organisms. The first direct evidence that histone modifications are involved in the differentiation process was provided by targeted deletion of the histone methyltransferase DOT1B which resulted in the inability of bloodstream stage parasites to differentiate to fly midgut stages. In this project, we will investigate changes in the nuclear architecture during host-induced differentiation, specifically the subnuclear distribution of histone modifications, and the assignment of specific modifications to the activity status of differentially regulated genes. We will test the hypothesis that chromatin remodeling is involved in the regulation of gene expression triggered by the host environment.