Zhao Hang, Li Di, Xiao Xue, Liu Cuifang, Chen Guifang, Su Xiaoyu, Yan Zhenxin, Gu Shijia, Wang Yizhou, Li Guohong, Feng Jianxun, Li Wei, Chen Ping, Yang Jiayi, Li Qing
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
iScience. 2023 Nov 28;27(1):108537. doi: 10.1016/j.isci.2023.108537. eCollection 2024 Jan 19.
The differentiation of embryonic stem cells (ESCs) begins with the transition from the naive to the primed state. The formative state was recently established as a critical intermediate between the two states. Here, we demonstrate the role of the histone chaperone FACT in regulating the naive-to-formative transition. We found that the Q265K mutation in the FACT subunit SSRP1 increased the binding of FACT to histone H3-H4, impaired nucleosome disassembly , and reduced the turnover of FACT on chromatin . Strikingly, mouse ESCs harboring this mutation showed elevated naive-to-formative transition. Mechanistically, the SSRP1-Q265K mutation enriched FACT at the enhancers of formative-specific genes to increase targeted gene expression. Together, these findings suggest that the turnover of FACT on chromatin is crucial for regulating the enhancers of formative-specific genes, thereby mediating the naive-to-formative transition. This study highlights the significance of FACT in fine-tuning cell fate transition during early development.
胚胎干细胞（ESC）的分化始于从原始态向启动态的转变。形成态最近被确立为这两种状态之间的关键中间状态。在此，我们展示了组蛋白伴侣FACT在调节原始态到形成态转变中的作用。我们发现FACT亚基SSRP1中的Q265K突变增加了FACT与组蛋白H3-H4的结合，损害了核小体的解体，并减少了FACT在染色质上的周转。引人注目的是，携带这种突变的小鼠胚胎干细胞显示出原始态到形成态转变的增加。从机制上讲，SSRP1-Q265K突变使FACT在形成态特异性基因的增强子处富集，从而增加靶向基因的表达。总之，这些发现表明FACT在染色质上的周转对于调节形成态特异性基因的增强子至关重要，从而介导原始态到形成态的转变。这项研究突出了FACT在早期发育过程中微调细胞命运转变的重要性。
