Histone methylation changes are required for life cycle progression in the human parasite Schistosoma mansoni

Epigenetic mechanisms and chromatin structure play an important role in development. Their impact is therefore expected to be strong in parasites with complex life cycles and multiple, strikingly different, developmental stages, i.e. developmental plasticity. Some studies have already described how the chromatin structure, through histone modifications, varies from a developmental stage to another in a few unicellular parasites. While H3K4me3 profiles remain relatively constant, H3K27 trimethylation and bivalent methylation show strong variation. Inhibitors (A366 and GSK343) of H3K27 histone methyltransferase activity in S. mansoni efficiently blocked miracidium to sporocyst transition indicating that H3K27 trimethylation is required for life cycle progression. As S. mansoni is a multicellular parasite that significantly affects both the health and economy of endemic areas, a better understanding of fluke developmental processes within the definitive host will likely highlight novel disease control strategies. Towards this goal, we also studied H4K20me1 in female cercariae and adults. In particular, we found that bivalent trimethylation of H3K4 and H3K27 at the transcription start site of genes is a landmark of the cercarial stage. In cercariae, H3K27me3 presence and strong enrichment in H4K20me1 over long regions (10–100 kb) is associated with development related genes. Here, we provide a broad overview of the chromatin structure of a metazoan parasite throughout its most important lifecycle stages. The five developmental stages studied here present distinct chromatin structures, indicating that histone methylation plays an important role during development. Hence, components of the histone methylation (and demethylation) machinery may provide suitable Schistosomiasis control targets.

表观遗传机制（epigenetic mechanisms）与染色质结构（chromatin structure）在生物体发育过程中发挥关键作用。因此，对于拥有复杂生命周期、多个显著迥异发育阶段（即发育可塑性（developmental plasticity））的寄生虫而言，这类机制的影响预计会尤为显著。已有部分研究针对少数单细胞寄生虫，阐述了染色质结构如何通过组蛋白修饰（histone modifications）在不同发育阶段间发生动态变化。尽管组蛋白H3赖氨酸4三甲基化（H3K4me3）的修饰谱相对稳定，但H3K27三甲基化（H3K27 trimethylation）与二价甲基化（bivalent methylation）则呈现出显著差异。针对曼氏血吸虫（Schistosoma mansoni，简称S. mansoni）体内H3K27组蛋白甲基转移酶（histone methyltransferase）活性的抑制剂（A366与GSK343）可有效阻断毛蚶（miracidium）向胞蚴（sporocyst）的发育转变，这表明H3K27三甲基化对于寄生虫的生命周期推进必不可少。由于曼氏血吸虫（S. mansoni）是一种多细胞寄生虫，会对流行区（endemic areas）的民众健康与经济发展造成严重影响，因此深入了解吸虫（fluke）在终末宿主（definitive host）体内的发育过程，有望为开发全新的疾病防控策略提供思路。为此，我们还针对雌性尾蚴（cercariae）与成虫体内的H4K20me1（组蛋白H4赖氨酸20单甲基化）展开了研究。具体而言，我们发现基因转录起始位点（transcription start site）处的H3K4与H3K27二价三甲基化修饰，是尾蚴阶段的标志性表观遗传特征。在尾蚴体内，H3K27me3的存在以及H4K20me1在长片段区域（10–100 kb）的显著富集，均与发育相关基因的表达密切相关。本研究全面梳理了一种后生动物寄生虫（metazoan parasite）在其关键生命周期各阶段的染色质结构特征。本次研究涉及的五个发育阶段均拥有各自独特的染色质结构，这表明组蛋白甲基化（histone methylation）修饰在寄生虫发育过程中发挥着关键作用。因此，组蛋白甲基化（及去甲基化）调控系统的相关组分，有望成为理想的血吸虫病（Schistosomiasis）防控靶点。