Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA.
Laboratory of Synthetic Embryology, The Rockefeller University, New York, NY 10065, USA.
Development. 2022 Oct 15;149(20). doi: 10.1242/dev.200335. Epub 2022 Jul 11.
Embryogenesis is guided by a limited set of signaling pathways dynamically expressed in different places. How a context-dependent signaling response is generated has been a central question of developmental biology, which can now be addressed with in vitro models of human embryos that are derived from embryonic stem cells (hESCs). Our previous work demonstrated that during early stages of hESC differentiation, cells chronicle signaling hierarchy. Only cells that have been exposed (primed) by WNT signaling can respond to subsequent activin exposure and differentiate to mesendodermal (ME) fates. Here, we show that WNT priming does not alter SMAD2 binding nor its chromatin opening but, instead, acts by inducing the expression of the SMAD2 co-factor EOMES. Expression of EOMES is sufficient to replace WNT upstream of activin-mediated ME differentiation, thus unveiling the mechanistic basis for priming and cellular memory in early development.
胚胎发生受有限的信号通路指导，这些信号通路在不同的地方动态表达。上下文相关的信号反应是如何产生的，这一直是发育生物学的核心问题，现在可以通过源自胚胎干细胞（hESCs）的体外人类胚胎模型来解决。我们之前的工作表明，在 hESC 分化的早期阶段，细胞会记录信号层次结构。只有那些已经暴露（启动）于 WNT 信号的细胞才能对随后的激活素暴露作出反应，并分化为中胚层（ME）命运。在这里，我们表明 WNT 启动不会改变 SMAD2 结合或其染色质开放，但相反，通过诱导 SMAD2 共同因子 EOMES 的表达起作用。EOMES 的表达足以在激活素介导的 ME 分化之前取代 WNT，从而揭示了早期发育中启动和细胞记忆的机制基础。
