Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China.
State key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, 200438, Shanghai, China.
Commun Biol. 2022 Apr 1;5(1):300. doi: 10.1038/s42003-022-03214-1.
TOX4 is one of the regulatory factors of PP1 phosphatases with poorly understood functions. Here we show that chromatin occupancy pattern of TOX4 resembles that of RNA polymerase II (Pol II), and its loss increases cellular level of C-terminal domain (CTD) phosphorylated Pol II but mainly decreases Pol II occupancy on promoters. In addition, elongation rate analyses by 4sUDRB-seq suggest that TOX4 restricts pause release and early elongation but promotes late elongation. Moreover, TT-seq analyses indicate that TOX4 loss mainly decreases transcriptional output. Mechanistically, TOX4 may restrict pause release through facilitating CTD serine 2 and DSIF dephosphorylation, and promote Pol II recycling and reinitiation through facilitating CTD serines 2 and 5 dephosphorylation. Furthermore, among the PP1 phosphatases, TOX4 preferentially binds PP1α and is capable of facilitating Pol II CTD dephosphorylation in vitro. These results lay the foundation for a better understanding of the role of TOX4 in transcriptional regulation.
TOX4 是 PP1 磷酸酶的调节因子之一，其功能尚未完全了解。在这里，我们表明 TOX4 的染色质占据模式类似于 RNA 聚合酶 II（Pol II），其缺失会增加细胞内 C 末端结构域（CTD）磷酸化 Pol II 的水平，但主要降低 Pol II 在启动子上的占据。此外，通过 4sUDRB-seq 进行的延伸率分析表明，TOX4 限制暂停释放和早期延伸，但促进晚期延伸。此外，TT-seq 分析表明，TOX4 的缺失主要降低转录输出。在机制上，TOX4 可能通过促进 CTD 丝氨酸 2 和 DSIF 的去磷酸化来限制暂停释放，并通过促进 CTD 丝氨酸 2 和 5 的去磷酸化来促进 Pol II 的循环和重新起始。此外，在 PP1 磷酸酶中，TOX4 优先结合 PP1α，并能够在体外促进 Pol II CTD 的去磷酸化。这些结果为更好地理解 TOX4 在转录调控中的作用奠定了基础。
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