A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment
A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment
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DOI：
10.1038/s41564-020-0674-4
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发表时间：
2020-02-24
影响因子：
28.3
通讯作者：
Hakimi, Mohamed-Ali
中科院分区：
文献类型：
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作者：
Farhat, Dayana C.;Swale, Christopher;Hakimi, Mohamed-Ali
弓形虫有一个复杂的生命周期，其典型特征是发生在脊椎动物中的无性发育和仅发生在猫科动物中的有性生殖，因此研究较少。发育转变依赖于基因表达模式的变化，最近的研究已经为染色质塑造者（包括组蛋白修饰）分配了角色，为每个给定的阶段建立特定的表观遗传程序。在这里，我们确定了T。gondii microrchidia（MORC）蛋白作为性承诺的上游转录抑制因子。MORC与Apetala 2（AP 2）转录因子形成复合物，可招募组蛋白脱乙酰酶HDAC 3，从而阻碍染色质在性阶段专门表达的基因处的可及性。我们发现，MORC耗竭细胞发生了显着的转录变化，导致一个特定的基因库的表达，并揭示了从无性增殖性分化的转变。MORC作为一个主调节器，指导二级AP2转录因子的分级表达，这些转录因子可能有助于生命周期的单向性。因此，MORC在T.弓形虫的生活史和有条件耗竭提供了一种体外研究弓形虫性发育的方法，并被提议作为T.来自刚地弓形虫（Toxoplasma gondii）的微睾吸虫（microrchidia，MORC）蛋白是调节寄生虫发育和性承诺的转录抑制物，并且其条件性耗尽为开发改进的体外系统以研究寄生虫性发育铺平了道路。
Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reproduction, which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.The microrchidia (MORC) protein from Toxoplasma gondii is a transcriptional repressor that regulates parasite development and sexual commitment, and its conditional depletion paves the way to develop improved in vitro systems to investigate parasite sexual development.