Ma Zhaoru, Tan Shuping, Lu Renhong, Chen Peixin, Hu Yukun, Yang Tenghui, Wu Hao, Zhu Zhexin, Guo Jiayi, Chen Xi, Yang Jian, Zhang Wensheng, Ye Ying
Cam-Su Genomic Resource Center, Medical College of Soochow University, Suzhou, China.
State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
J Biol Chem. 2025 Feb;301(2):108140. doi: 10.1016/j.jbc.2024.108140. Epub 2024 Dec 25.
Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) are pluripotent stem cells derived from preimplantation and postimplantation embryos, respectively. These cells are capable of interconversion through manipulation of key transcription factors and signaling pathways. While BRG1/BRM-associated factor (BAF) chromatin remodeling complexes are known to play crucial roles in ESC self-renewal and pluripotency, their roles in EpiSCs and their interconversion with ESCs remain unclear. This study demonstrates that the LIF/STAT3 and Wnt signaling pathways, in conjunction with canonical BAF (cBAF) and polycomb repressive complex two complexes, inhibit EpiSC gene expression, thereby preventing ESCs from converting to EpiSCs. Upon removal of LIF, the reduced LIF/STAT3 signaling lifts this inhibition, increasing TGF/nodal pathway activity. Subsequently, the cBAF complex facilitates ESC to EpiSC conversion by promoting EpiSC gene expression. Furthermore, unlike cBAF, inhibition of the ncBAF complex downregulates TGF-β signaling, thereby hindering both ESC to EpiSC conversion and EpiSC maintenance. Moreover, this study revealed the dual mechanisms, methylating histone or non-histone protein STAT3, by which polycomb repressive complex two components participate in the regulation of ESCs to EpiSCs. This research elucidates the interplay between distinct BAF complexes and specific signaling pathways in regulating the conversion and maintenance of ESCs and EpiSCs.
小鼠胚胎干细胞（ESCs）和上胚层干细胞（EpiSCs）是分别源自植入前和植入后胚胎的多能干细胞。这些细胞能够通过操纵关键转录因子和信号通路进行相互转化。虽然已知BRG1/BRM相关因子（BAF）染色质重塑复合物在ESC自我更新和多能性中起关键作用，但其在EpiSCs中的作用以及它们与ESCs的相互转化仍不清楚。本研究表明，LIF/STAT3和Wnt信号通路与经典BAF（cBAF）和多梳抑制复合物二复合物一起，抑制EpiSC基因表达，从而阻止ESCs转化为EpiSCs。去除LIF后，降低的LIF/STAT3信号解除这种抑制，增加TGF/nodal信号通路活性。随后，cBAF复合物通过促进EpiSC基因表达促进ESC向EpiSC转化。此外，与cBAF不同，抑制ncBAF复合物会下调TGF-β信号，从而阻碍ESC向EpiSC转化和EpiSC维持。此外，本研究揭示了多梳抑制复合物二组分参与ESC向EpiSC调控的双重机制，即甲基化组蛋白或非组蛋白蛋白STAT3。这项研究阐明了不同BAF复合物与特定信号通路之间在调节ESC和EpiSC转化及维持中的相互作用。
