Qi Zhihong, Wang Fang, Yu Guotao, Wang Di, Yao Yingpeng, You Menghao, Liu Jingjing, Liu Juanjuan, Sun Zhen, Ji Ce, Xue Yuanchao, Yu Shuyang
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Sci Adv. 2021 Apr 16;7(16). doi: 10.1126/sciadv.abf0753. Print 2021 Apr.
The underlying mechanisms of thymocyte maturation remain largely unknown. Here, we report that serine/arginine-rich splicing factor 1 (SRSF1) intrinsically regulates the late stage of thymocyte development. Conditional deletion of SRSF1 resulted in severe defects in maintenance of late thymocyte survival and a blockade of the transition of TCRβCD24CD69 immature to TCRβCD24CD69 mature thymocytes, corresponding to a notable reduction of recent thymic emigrants and diminished periphery T cell pool. Mechanistically, SRSF1 regulates the gene networks involved in thymocyte differentiation, proliferation, apoptosis, and type I interferon signaling pathway to safeguard T cell intrathymic maturation. In particular, SRSF1 directly binds and regulates and expression via alternative splicing in response to type I interferon signaling. Moreover, forced expression of interferon regulatory factor 7 rectifies the defects in SRSF1-deficient thymocyte maturation via restoring expression of type I interferon-related genes. Thus, our work provides new insight on SRSF1-mediated posttranscriptional regulatory mechanism of thymocyte development.
胸腺细胞成熟的潜在机制在很大程度上仍然未知。在此，我们报道富含丝氨酸/精氨酸的剪接因子1（SRSF1）内在地调节胸腺细胞发育的后期阶段。SRSF1的条件性缺失导致晚期胸腺细胞存活维持方面的严重缺陷，以及TCRβCD24CD69未成熟胸腺细胞向TCRβCD24CD69成熟胸腺细胞转变的阻滞，这对应于近期胸腺迁出细胞的显著减少和外周T细胞库的缩小。从机制上讲，SRSF1调节参与胸腺细胞分化、增殖、凋亡和I型干扰素信号通路的基因网络，以保障T细胞在胸腺内的成熟。特别是，SRSF1响应I型干扰素信号，通过可变剪接直接结合并调节 和 的表达。此外，干扰素调节因子7的强制表达通过恢复I型干扰素相关基因的表达来纠正SRSF1缺陷型胸腺细胞成熟中的缺陷。因此，我们的工作为SRSF1介导的胸腺细胞发育的转录后调控机制提供了新的见解。
