Gastrulation in the early postimplantation stage mammalian embryo begins when epiblast cells ingress to form the primitive streak or develop as the embryonic ectoderm. The DNA dioxygenase Tet1 is highly expressed in the epiblast and yet continues to regulate lineage specification during gastrulation when its expression is diminished. Here, we show how Tet1 plays a pivotal role upstream of germ layer lineage bifurcation. During the transition from naive pluripotency to lineage priming, a global reconfiguration redistributes Tet1 from Oct4-cobound promoters to distal regulatory elements at lineage differentiation genes, which are distinct from high-affinity sites engaged by Oct4. An altered chromatin landscape in Tet1-deficient primed epiblast-like cells is associated with enhanced Oct4 expression and binding to Nodal and Wnt target genes, resulting in collaborative signals that enhance mesendodermal and inhibit neuroectodermal gene expression during lineage segregation. A permissive role for Tet1 in neural fate induction involves Zic2-dependent engagement at neural target genes at lineage priming, is dependent on the signaling environment during gastrulation, and impacts neural tube closure after gastrulation. Our findings provide mechanistic information for epigenetic integration of pluripotency and signal-induced differentiation cues.

中文翻译：

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在致敏的多能性过程中，TET1对细菌层谱系选择的协调。

当表皮细胞进入形成原始条纹或发展为胚外胚层时，在胚胎植入后早期的胚期开始。DNA双加氧酶Tet1在上皮细胞中高度表达，但当其表达减少时，在胃形成过程中仍继续调节谱系规格。在这里，我们显示Tet1如何在胚芽谱系分支的上游发挥关键作用。在从幼稚多能性向谱系启动的过渡过程中，全局重新配置将Tet1从Oct4结合的启动子重新分布到谱系分化基因的远端调控元件，这不同于Oct4参与的高亲和力位点。Tet1缺陷的上皮成细胞样细胞中染色质景观的改变与增强的Oct4表达以及与Nodal和Wnt靶基因的结合有关，导致协同信号增强谱系分离过程中的中胚层并抑制神经外胚层基因的表达。Tet1在神经命运诱导中的许可作用涉及沿袭启动时神经靶基因的Zic2依赖性参与，取决于胃泌乳过程中的信号传导环境，并影响胃泌乳后神经管的闭合。我们的发现为多能性和信号诱导分化线索的表观遗传学整合提供了机械信息。并影响胃造瘘后神经管的闭合。我们的发现为多能性和信号诱导分化线索的表观遗传学整合提供了机械信息。并影响胃造瘘后神经管的闭合。我们的发现为多能性和信号诱导分化线索的表观遗传学整合提供了机械信息。