Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells
Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells
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DOI：
10.1038/s41467-019-12720-6
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发表时间：
2019-10-18
影响因子：
16.6
通讯作者：
Kim, Jonghwan
中科院分区：
文献类型：
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作者：
Lee, Bum-Kyu;Jang, Yu Jin;Kim, Jonghwan
滋养外胚层 (TE) 谱系发育对于正确着床、胎盘和健康妊娠至关重要。然而，只有少数 TE 特异性转录因子 (TF) 得到了系统的表征，阻碍了我们对该过程的理解。为了阐明 TE 发育的调控机制，我们在这里绘制了滋养层干细胞 (TSC) 中的超级增强子 (SE) 作为模型。我们发现了突出的 TE 特异性主 TF（Cdx2、Gata3 和 Tead4），以及超过 150 个以前未涉及 TE 谱系的 TF，它们与 SE 相关。绘制 27 个 SE 预测转录因子的靶标图谱揭示了高度交织的转录调控电路。有趣的是，SE 预测的 TF 显示出 4 种不同的表达模式，在 TSC 分化过程中其目标会发生动态变化。此外，TF 子集的耗尽会导致胎盘中特殊细胞类型的标记物失调，这表明在 TE 分化过程中发挥作用。总的来说，我们描述了一个扩展的 TE 特定监管网络，为理解 TE 谱系发展和安置提供了一个框架。
Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.