Mammalian pluripotent cells first segregate into neuroectoderm (NE), or mesoderm and endoderm (ME), characterized by lineage-specific transcriptional programs and chromatin states. To date, the relationship between transcription factor activities and dynamic chromatin changes that guide cell specification remains ill-defined. In this study, we employ mouse embryonic stem cell differentiation toward ME lineages to reveal crucial roles of the Tbx factor Eomes to globally establish ME enhancer accessibility as the prerequisite for ME lineage competence and ME-specific gene expression. EOMES cooperates with the SWItch/sucrose non-fermentable (SWI/SNF) complex to drive chromatin rewiring that is essential to overcome default NE differentiation, which is favored by asymmetries in chromatin accessibility at pluripotent state. Following global ME enhancer remodeling, ME-specific gene transcription is controlled by additional signals such as Wnt and transforming growth factor β (TGF-β)/NODAL, as a second layer of gene expression regulation, which can be mechanistically separated from initial chromatin remodeling activities.

中文翻译：

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EOMES 通过 SWI/SNF 介导的整体增强子重塑建立中胚层和内胚层分化潜力


哺乳动物多能细胞首先分离成神经外胚层 （NE） 或中胚层和内胚层 （ME），其特征是谱系特异性转录程序和染色质状态。迄今为止，转录因子活性与指导细胞规格的动态染色质变化之间的关系仍不明确。在这项研究中，我们利用小鼠胚胎干细胞向 ME 谱系分化来揭示 Tbx 因子 Eomes 的关键作用，以在全球范围内建立 ME 增强子可及性作为 ME 谱系能力和 ME 特异性基因表达的先决条件。EOMES 与 SWItch/蔗糖不可发酵 （SWI/SNF） 复合物合作，驱动染色质重新布线，这对于克服默认的 NE 分化至关重要，这在多能状态下染色质可及性的不对称性中受到青睐。在整体 ME 增强子重塑后，ME 特异性基因转录受 Wnt 和转化生长因子 β （TGF-β）/NODAL 等附加信号控制，作为基因表达调控的第二层，它可以在机制上与初始染色质重塑活性分离。