Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.
Nat Commun. 2024 Jul 29;15(1):6365. doi: 10.1038/s41467-024-50144-z.
Cell fate decisions remain poorly understood at the molecular level. Embryogenesis provides a unique opportunity to analyze molecular details associated with cell fate decisions. Works based on model organisms have provided a conceptual framework of genes that specify cell fate control, for example, transcription factors (TFs) controlling processes from pluripotency to immunity. How TFs specify cell fate remains poorly understood. Here we report that SALL4 relies on NuRD (nucleosome-remodeling and deacetylase complex) to interpret BMP4 signal and decide cell fate in a well-controlled in vitro system. While NuRD complex cooperates with SALL4 to convert mouse embryonic fibroblasts or MEFs to pluripotency, BMP4 diverts the same process to an alternative fate, PrE (primitive endoderm). Mechanistically, BMP4 signals the dissociation of SALL4 from NuRD physically to establish a gene regulatory network for PrE. Our results provide a conceptual framework to explore the rich landscapes of cell fate choices intrinsic to development in higher organisms involving morphogen-TF-chromatin modifier pathways.
细胞命运决定在分子水平上仍未得到很好的理解。胚胎发生为分析与细胞命运决定相关的分子细节提供了一个独特的机会。基于模式生物的研究已经提供了一个控制细胞命运的基因概念框架，例如，转录因子（TFs）控制从多能性到免疫的过程。TFs 如何指定细胞命运仍然知之甚少。在这里，我们报告 SALL4 依赖 NuRD（核小体重塑和去乙酰化酶复合物）来解释 BMP4 信号，并在一个很好控制的体外系统中决定细胞命运。虽然 NuRD 复合物与 SALL4 合作将小鼠胚胎成纤维细胞或 MEFs 转化为多能性，但 BMP4 将相同的过程引导到另一种命运，即 PrE（原始内胚层）。在机制上，BMP4 信号促使 SALL4 从 NuRD 上物理解离，从而为 PrE 建立一个基因调控网络。我们的研究结果为探索涉及形态发生素-TF-染色质修饰途径的高等生物发育内在的丰富细胞命运选择景观提供了一个概念框架。
