Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
mSphere. 2021 Feb 3;6(1):e01220-20. doi: 10.1128/mSphere.01220-20.
The human malaria parasite encodes a single ortholog of heterochromatin protein 1 (PfHP1) that plays a crucial role in the epigenetic regulation of various survival-related processes. PfHP1 is essential for parasite proliferation and the heritable silencing of genes linked to antigenic variation, host cell invasion, and sexual conversion. Here, we employed CRISPR/Cas9-mediated genome editing combined with the DiCre/loxP system to investigate how the PfHP1 chromodomain (CD), hinge domain, and chromoshadow domain (CSD) contribute to overall PfHP1 function. We show that the 76 C-terminal residues are responsible for targeting PfHP1 to the nucleus. Furthermore, we reveal that each of the three functional domains of PfHP1 are required for heterochromatin formation, gene silencing, and mitotic parasite proliferation. Finally, we discovered that the hinge domain and CSD of HP1 are functionally conserved between and , a related malaria parasite infecting rodents. In summary, our study provides new insights into PfHP1 function and offers a tool for further studies on epigenetic regulation and life cycle decision in malaria parasites. Malaria is caused by unicellular species parasites that repeatedly invade and replicate inside red blood cells. Some blood-stage parasites exit the cell cycle and differentiate into gametocytes that are essential for malaria transmission via the mosquito vector. Epigenetic control mechanisms allow the parasites to alter the expression of surface antigens and to balance the switch between parasite multiplication and gametocyte production. These processes are crucial to establish chronic infection and optimize parasite transmission. Here, we performed a mutational analysis of heterochromatin protein 1 (HP1) in We demonstrate that all three domains of this protein are indispensable for the proper function of HP1 in parasite multiplication, heterochromatin formation, and gene silencing. Moreover, expression of chimeric proteins revealed the functional conservation of HP1 proteins between different species. These results provide new insight into the function and evolution of HP1 as an essential epigenetic regulator of parasite survival.
人类疟疾寄生虫编码单个异染色质蛋白 1（PfHP1）的同源物，该蛋白在各种与生存相关的过程的表观遗传调控中发挥关键作用。PfHP1 对于寄生虫增殖以及与抗原变异、宿主细胞入侵和有性转换相关的基因的可遗传性沉默至关重要。在这里，我们使用 CRISPR/Cas9 介导的基因组编辑结合 DiCre/loxP 系统来研究 PfHP1 染色质结构域（CD）、铰链域和染色质阴影域（CSD）如何共同促进 PfHP1 的整体功能。我们表明，76 个 C 末端残基负责将 PfHP1 靶向细胞核。此外，我们揭示 PfHP1 的三个功能域中的每一个都对于异染色质形成、基因沉默和有丝分裂寄生虫增殖都是必需的。最后，我们发现 HP1 的铰链域和 CSD 在 和 之间具有功能保守性， 是一种感染啮齿动物的相关疟疾寄生虫。总之，我们的研究提供了 PfHP1 功能的新见解，并为进一步研究疟疾寄生虫中的表观遗传调控和生命周期决策提供了工具。疟疾是由单细胞寄生虫引起的，这些寄生虫反复入侵和复制红细胞。一些血期寄生虫退出细胞周期并分化为配子体，这对于通过蚊子媒介传播疟疾至关重要。表观遗传控制机制允许寄生虫改变表面抗原的表达，并平衡寄生虫增殖和配子体产生之间的转换。这些过程对于建立慢性感染和优化寄生虫传播至关重要。在这里，我们对 中的异染色质蛋白 1（HP1）进行了突变分析。我们证明该蛋白的所有三个结构域对于 HP1 在寄生虫增殖、异染色质形成和基因沉默中的正确功能都是必不可少的。此外，嵌合蛋白的表达揭示了不同 物种之间 HP1 蛋白的功能保守性。这些结果为 HP1 作为寄生虫生存的重要表观遗传调节剂的功能和进化提供了新的见解。
