美国波士顿儿童医院Zhang Yi团队近日取得一项新成果。他们的最新研究探明，转录因子GABPA是初始多能性的主要调控因子。这一研究成果发表在2025年1月2日出版的国际学术期刊《自然—细胞生物学》上。

据介绍，初始多能性的建立是一个持续的过程，从内细胞团（ICM）的产生开始，然后分化为外胚层（EPI）。最近的研究揭示了ICM形成的关键转录因子（TFs），但哪些TFs启动EPI规范仍不清楚。

通过构建一个靶向的快速蛋白降解系统，研究小组发现GABPA不仅是ZGA的主要调控因子，而且在E3.5到E4.5过渡期间调控47%的EPI基因，是初始多能性建立所需的主EPI指示物。

染色质结合动力学分析表明，GABPA控制EPI的形成至少部分是通过在E3.5时，结合由多能性调节因子TFAP2C和SOX2占据的ICM基因启动子，在E4.5时建立初始多能性。他们的研究不仅揭示了GABPA是一个主要的多能性调节因子，而且还支持了哺乳动物多能性的建立，需要一个动态的、逐步的多TFs调节网络的观点。

附：英文原文

Title: The transcription factor GABPA is a master regulator of naive pluripotency

Author: Zhou, Chengjie, Wang, Meng, Zhang, Chunxia, Zhang, Yi

Issue&Volume: 2025-01-02

Abstract: The establishment of naive pluripotency is a continuous process starting with the generation of inner cell mass (ICM) that then differentiates 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 naive 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 naive 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-TF regulatory network.

DOI: 10.1038/s41556-024-01554-0

Source: https://www.nature.com/articles/s41556-024-01554-0