T. Nicolai Siegel小组报道了非洲锥虫抗原表达层次的基因组决定因素。2025年3月12日出版的《自然》发表了这项成果。

在这里，该研究团队报告建立了一个高灵敏度的单细胞RNA测序方法的模式原生动物寄生虫布鲁氏锥虫。这种方法揭示了在开关事件中发生在单个细胞中的基因组重排。他们的数据显示，在转录的抗原编码基因（抗原转换的重要触发器）发生双链断裂后，修复机制的类型和由此产生的抗原表达取决于基因组中同源修复模板的可用性。当这样的模板可用时，修复通过片段基因转换进行，产生新的马赛克抗原编码基因。相反，在缺乏合适模板的情况下，来自基因组不同部分的端粒邻近抗原编码基因被断裂诱导复制激活。他们的研究结果表明，修复序列可用性在抗原选择机制中起着关键作用。

此外，他们的研究证明了高度敏感的单细胞RNA测序方法在检测驱动单细胞水平转录变化的基因组重排方面的能力。

据介绍，抗原变异是一种以多种不同病原体为主题的免疫逃避策略。它涉及在整个感染过程中不同抗原表达的周期性、非随机转换。观察到的抗原表达层次结构是如何实现的仍然是一个谜。揭示这一过程的一个关键挑战是无法在开关事件中跟踪单个细胞的转录组变化和潜在的基因组重排。

附：英文原文

Title: Genomic determinants of antigen expression hierarchy in African trypanosomes

Author: Keneskhanova, Zhibek, McWilliam, Kirsty R., Cosentino, Ral O., Barcons-Simon, Anna, Dobrynin, Atai, Smith, Jaclyn E., Subota, Ines, Mugnier, Monica R., Colom-Tatch, Maria, Siegel, T. Nicolai

Issue&Volume: 2025-03-12

Abstract: Antigenic variation is an immune evasion strategy used by many different pathogens. It involves the periodic, non-random switch in the expression of different antigens throughout an infection. How the observed hierarchy in antigen expression is achieved has remained a mystery1,2. A key challenge in uncovering this process has been the inability to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. Here we report the establishment of a highly sensitive single-cell RNA sequencing approach for the model protozoan parasite Trypanosoma brucei. This approach has revealed genomic rearrangements that occur in individual cells during a switch event. Our data show that following a double-strand break in the transcribed antigen-coding gene—an important trigger for antigen switching—the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated by break-induced replication. Our results show the critical role of repair sequence availability in the antigen selection mechanism. Furthermore, our study demonstrates the power of highly sensitive single-cell RNA sequencing methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level.

DOI: 10.1038/s41586-025-08720-w

Source: https://www.nature.com/articles/s41586-025-08720-w