Zhou Chengjie, Wang Meng, Zhang Chunxia, Zhang Yi
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
bioRxiv. 2024 Nov 21:2024.11.11.623003. doi: 10.1101/2024.11.11.623003.
The establishment of naïve pluripotency is a continuous process starting with the generation of inner cell mass (ICM) which then differentiating into epiblast (EPI). Recent studies have revealed key transcription factors (TFs) for ICM formation, but which TFs initiate EPI specification remains unknown. Here, using a targeted rapid protein degradation system, we show that GABPA is not only a regulator of major ZGA, but also a master EPI specifier required for naïve pluripotency establishment by regulating 47% of EPI genes during E3.5 to E4.5 transition. Chromatin binding dynamics analysis suggests that GABPA controls EPI formation at least partly by binding to the ICM gene promoters occupied by the pluripotency regulators TFAP2C and SOX2 at E3.5 to establish naïve pluripotency at E4.5. Our study not only uncovers GABPA as a master pluripotency regulator, but also supports the notion that mammalian pluripotency establishment requires a dynamic and stepwise multi-TFs regulatory network.
幼稚多能性的建立是一个连续的过程，始于内细胞团（ICM）的产生，随后内细胞团分化为上胚层（EPI）。最近的研究揭示了ICM形成的关键转录因子（TFs），但启动EPI特化的TFs仍然未知。在这里，我们使用靶向快速蛋白质降解系统表明，GABPA不仅是主要合子基因组激活（ZGA）的调节因子，而且是幼稚多能性建立所需的主要EPI决定因子，它在E3.5至E4.5转变期间调控47%的EPI基因。染色质结合动力学分析表明，GABPA至少部分通过结合E3.5时多能性调节因子TFAP2C和SOX2占据的ICM基因启动子来控制EPI形成，从而在E4.5时建立幼稚多能性。我们的研究不仅揭示了GABPA作为主要多能性调节因子，而且支持了哺乳动物多能性建立需要动态且逐步的多TFs调控网络这一观点。
