Yang Jiao, Dan Jiameng, Zhao Nannan, Liu Linlin, Wang Huasong, Liu Qiangqiang, Wang Lingling, Li Jie, Wu Yiwei, Chen Feilong, Fu Weilun, Liu Fei, Lin Meiqi, Zhang Weiyu, Chen Fuquan, Liu Xinqi, Lu Xinyi, Chen Quan, Wu Xudong, Niu Yuyu, Yang Na, Zhu Yushan, Long Jiafu, Liu Lin
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300350, China.
Department of Cell Biology and Genetics, Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300350, China.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2407490121. doi: 10.1073/pnas.2407490121. Epub 2024 Dec 20.
Zygotic genome activation occurs in two-cell (2C) embryos, and a 2C-like state is also activated in sporadic (~1%) naïve embryonic stem cells in mice. Elevated chromatin accessibility is critical for the 2C-like state to occur, yet the underlying molecular mechanisms remain elusive. Zscan4 exhibits burst expression in 2C embryos and 2C-like cells. Here, we show that Zscan4 mediates chromatin remodeling to promote the chromatin accessibility for achieving the 2C-like state. Through coimmunoprecipitation/mass spectrometry, we identified that Zscan4 interacts with the corepressors Kap1/Trim28, Lsd1, and Hdac1, also with H3K9me3 modifiers Suv39h1/2, to transiently form a repressive chromatin complex. Then, Zscan4 mediates the degradation of these chromatin repressors by recruiting Trim25 as an E3 ligase, enabling the ubiquitination of Lsd1, Hdac1, and Suv39h1/2. Degradation of the chromatin repressors promotes the chromatin accessibility for activation of the 2C-like state. These findings reveal the molecular insights into the roles of Zscan4 in promoting full activation of the 2C-like state.
合子基因组激活发生在二细胞（2C）胚胎中，并且在小鼠中散发性（约1%）的原始胚胎干细胞中也会激活类似2C的状态。染色质可及性的升高对于类似2C状态的发生至关重要，但其潜在的分子机制仍不清楚。Zscan4在2C胚胎和类似2C的细胞中呈现爆发性表达。在此，我们表明Zscan4介导染色质重塑，以促进染色质可及性从而实现类似2C的状态。通过免疫共沉淀/质谱分析，我们鉴定出Zscan4与共抑制因子Kap1/Trim28、Lsd1和Hdac1相互作用，也与H3K9me3修饰因子Suv39h1/2相互作用，以瞬时形成一种抑制性染色质复合物。然后，Zscan4通过招募作为E3连接酶的Trim25介导这些染色质抑制因子的降解，使Lsd1、Hdac1和Suv39h1/2发生泛素化。染色质抑制因子的降解促进了染色质可及性，以激活类似2C的状态。这些发现揭示了Zscan4在促进类似2C状态完全激活中的作用的分子见解。
