Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200052, China.
Commun Biol. 2023 Jun 7;6(1):613. doi: 10.1038/s42003-023-04992-y.
HMG protein Tox4 is a regulator of PP1 phosphatases with unknown function in development. Here we show that Tox4 conditional knockout in mice reduces thymic cellularity, partially blocks T cell development, and decreases ratio of CD8 to CD4 through decreasing proliferation and increasing apoptosis of CD8 cells. In addition, single-cell RNA-seq discovered that Tox4 loss also impairs proliferation of the fast-proliferating double positive (DP) blast population within DP cells in part due to downregulation of genes critical for proliferation, notably Cdk1. Moreover, genes with high and low expression level are more dependent on Tox4 than genes with medium expression level. Mechanistically, Tox4 may facilitate transcriptional reinitiation and restrict elongation in a dephosphorylation-dependent manner, a mechanism that is conserved between mouse and human. These results provide insights into the role of TOX4 in development and establish it as an evolutionarily conserved regulator of transcriptional elongation and reinitiation.
HMG 蛋白 Tox4 是 PP1 磷酸酶的调节剂，但其在发育中的功能未知。本文作者表示，在小鼠中条件性敲除 Tox4 会减少胸腺细胞的数量，部分阻断 T 细胞的发育，并通过减少 CD8 细胞的增殖和增加其凋亡来降低 CD8 与 CD4 的比例。此外，单细胞 RNA-seq 发现 Tox4 的缺失也会损害 DP 细胞中快速增殖的双阳性（DP） blast 群体的增殖，这部分是由于增殖相关关键基因（尤其是 Cdk1）的下调。此外，高表达和低表达水平的基因比中表达水平的基因更依赖 Tox4。从机制上讲，Tox4 可能通过去磷酸化依赖的方式促进转录重新起始和限制延伸，这种机制在小鼠和人类中是保守的。这些结果为 TOX4 在发育中的作用提供了新的见解，并确立了其作为转录延伸和重新起始的进化保守调控因子的地位。
