文献类型： 外文期刊

第一作者： Sun, Li-Xiu

作者： Sun, Li-Xiu;Wang, Meng;Zhang, Tian-Yu;Zhang, Zhi-Wei;Fu, Bao-Quan;Wang, Jin-Lei;Sun, Li-Xiu;Zhang, Tian-Yu;Liu, Guo-Hua;Elsheikha, Hany M.;Zheng, Xiao-Nan;Zhu, Xing-Quan

作者机构：

关键词： Toxoplasma gondii; AP2X-1; HDAC3/MORC complex; gene expression; sexual development; transcription

期刊名称：MBIO （ 影响因子：4.7； 五年影响因子：5.5 ）

ISSN：

年卷期： 2025 年 16 卷 9 期

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收录情况： SCI

摘要： Toxoplasma gondii is a widespread protozoan with a complex life cycle, characterized by transitions between various hosts and developmental stages, each tailored to a specific niche within its host. However, the regulatory mechanisms governing these life cycle transitions are not well understood. In this study, we investigated the AP2 factor AP2X-1, which is expressed during the tachyzoite and bradyzoite stages but decreases in the mature merozoite stage. Knockout of ap2X-1 significantly impaired tachyzoite invasion and replication while increasing the frequency of bradyzoite differentiation. As a component associated with the HDAC3/MORC complex, loss of ap2X-1 led to the upregulation of bradyzoite- and sexual stage-specific genes. Single-cell sequencing revealed that the ap2X-1 knockout strain exhibited a mixed population of tachyzoite-, bradyzoite-, merozoite-, and sporozoite-like parasites. Cleavage under targets and tagmentation analysis revealed a substantial overlap between AP2X-1 and the HDAC3/MORC complex at the promoters of bradyzoite- and sexual stage-specific genes. Additionally, assay for transposase-accessible chromatin with high-throughput sequencing analysis demonstrated that AP2X-1 influences chromatin compaction and accessibility, suggesting that AP2X-1 may modulate the function of the HDAC3/MORC complex to facilitate the repression of bradyzoite differentiation and sexual commitment. Loss of ap2X-1 resulted in significant attenuation of T. gondii virulence and decreased brain cyst formation in vivo. These findings identify AP2X-1 as a critical negative regulator of T. gondii sexual development.IMPORTANCEToxoplasma gondii undergoes a complex life cycle characterized by alternating developmental stages. The genetic reprogramming mechanisms driving these stage transitions remain largely unknown. In this study, we identified the AP2 factor AP2X-1 as a critical regulator important for T. gondii growth and life cycle progression. Our findings suggest that AP2X-1 functions as a repressor by modulating the function or influencing the association of the HDAC3/MORC complex at the promoters of bradyzoite- and sexual stage-specific genes, leading to chromatin compaction, restricting DNA accessibility and thereby repressing the transcription of genes required for bradyzoite formation and sexual commitment. Deletion of ap2X-1 significantly reduced T. gondii virulence and its ability to form brain cysts. These findings reveal a previously unknown regulatory pathway controlling sexual development in T. gondii, providing new insights into its underlying mechanisms.

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