Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers
Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers
复制标题
Hippo-YAP 信号通过调节超级增强子的形成来控制小鼠胚胎干细胞的谱系分化。
DOI：
10.1093/nar/gkaa482
复制
发表时间：
2020-07-27
影响因子：
14.9
通讯作者：
Yuan, Ping
中科院分区：
文献类型：
--
作者：
Sun, Xiang;Ren, Zhijun;Yuan, Ping
Hippo-YAP信号通路在多能干细胞的早期谱系分化中发挥作用，但详细机制仍不清楚。我们发现，小鼠胚胎干细胞 (ESC) 中 Hippo 信号传导的两个关键成分 Mst1 和 Mst2 的敲除 (KO) 会导致向中内胚层谱系的分化中断。为了进一步揭示潜在的调控机制，我们使用针对 YAP、ESC 主转录因子和一些特征性组蛋白修饰标记的抗体进行了一系列 ChIP-seq 实验，并分别使用野生型和 Mst KO 样本在 ES 和第 4 天胚状体阶段进行了 RNA-seq 测定。我们证明 YAP 在 ESC 中优先与超级增强子 (SE) 标记（例如 Nanog、Sox2、Oct4 和 H3K27ac）共定位。 Mst KO ESC 中核 YAP 的过度激活促进了 Nanog、Sox2 和 Oct4 的结合，以及 YAP 结合位点上的 H3K27ac 修饰。此外，Mst耗尽导致新的SE形成和谱系相关基因上液-液相分离Med1凝聚物的增强，导致这些基因的上调和ESC分化的扭曲。我们的研究揭示了 Hippo-YAP 信号通路如何决定 ESC 谱系分化的新机制。
Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation.