マラリア原虫の発達におけるヘテロクロマチンの役割

タイトル: Heterochromatin dynamics during the initial stages of sexual development in Plasmodium falciparum

概要: Asexual replication of Plasmodium falciparum in the human blood results in exponential parasite growth and causes all clinical symptoms of malaria. However, at each round of the replicative cycle, some parasites convert into sexual precursors called gametocytes, which are essential for transmission to mosquito vectors. After sexual conversion, parasites develop through the sexual ring stage and then gametocyte stages I to V before they are infective to mosquitoes. Heterochromatin, a type of chromatin generally refractory to gene expression, plays an important role in the regulation of sexual conversion by silencing the master regulator of the process, PfAP2-G, in asexual parasites. Additionally, previous reports have described changes in the genome-wide distribution of heterochromatin in stage II/III or older gametocytes, including expansion of heterochromatin at several subtelomeric regions and reduced occupancy at a few specific loci. However, it is not known if these changes occur concomitantly with sexual conversion or at a later time during gametocyte development. Using a transgenic line in which sexual conversion can be conditionally induced, here we show that the genome-wide distribution of heterochromatin at the initial stages of sexual development (i.e., sexual rings and stage I gametocytes) is almost identical to parasites at asexual blood stages, and major changes do not occur until stage II/III. We also show that transcriptional changes associated with sexual development typically precede, rather than follow, changes in heterochromatin occupancy at their loci, which raises the possibility that PfAP2-G operates as a pioneer factor. IMPORTANCEEpigenetic processes and chromatin structure play an important role in the regulation of gene expression in malaria parasites. In particular, a type of chromatin called heterochromatin is involved in the regulation (silencing) of many genes. Parasite sexual development is essential for transmission to mosquito vectors. Here we characterised the global distribution of heterochromatin at different stages of sexual development, and found that initially it is identical to asexual blood stages, but at later transmission stages it is altered. This informs about the putative roles of general heterochromatin redistribution in parasite life cycle progression. By integrating multi-omic datasets, we also found that changes in the expression of several genes precede changes in their heterochromatin occupancy. This indicates that during sexual development some genes can be activated in spite of having heterochromatin.