Deciphering a distinct regulatory network of TEAD4, CDX2 and GATA3 in humans for trophoblast transition from embryonic stem cells
Deciphering a distinct regulatory network of TEAD4, CDX2 and GATA3 in humans for trophoblast transition from embryonic stem cells
复制标题
破译人类胚胎干细胞滋养层转变中 TEAD4、CDX2 和 GATA3 的独特调控网络
DOI：
10.1016/j.bbamcr.2020.118736
复制
发表时间：
2020
影响因子：
5.1
通讯作者：
Wei Yanxing✳
中科院分区：
文献类型：
--
作者：
Xiao Lu;Ma Lishi;Wang Zhijian;Yu Yanhong;Lye J. Stephen;Shan Yongli✳;Wei Yanxing✳
胎盘是胎儿的重要器官，但在人类中，胎盘对功能性滋养层细胞系形成的调控机制仍不清楚。尽管TEAD4及其下游靶点CDX2和GATA3在小鼠中广为人知，但尚未在人类模型中确定。在这项工作中，我们使用了BAP(BMP4，A83-01和PD173074)处理的人胚胎干细胞(HESCs)的滋养层细胞转化的人体模型，并进行了TEAD4、CDX2或GATA3的多次功能获得和丧失测试，以研究它们在这一过程中的作用。尽管缺失了TEAD4的hESCs保持了多能性，但它们的滋养层转移潜能减弱了。过度表达TEAD4、CDX2或GATA3可以挽救这种受损的滋养细胞过渡。此外，hESCs的滋养层转变也受到CDX2基因敲除的影响，但不受GATA3基因缺失的影响。然而，CDX2过表达的hESCs保持多能性，而GATA3在hESCs中过表达导致自发分化，包括滋养细胞系。简而言之，我们使用BAP处理的hESCs的滋养层细胞过渡的人类模型的发现揭示了TEAD4、CDX2和GATA在人类中的转录作用，这与在小鼠中的不同。我们希望这一证据有助于理解调控人类滋养层细胞发育的独特转录网络。
The placenta is an essential organ for the fetus, but its regulatory mechanism for formation of functional trophoblast lineage remains elusive in humans. Although widely known in mice, TEAD4 and its downstream targets CDX2 and GATA3 have not been determined in human models. In this work, we used a human model of trophoblast transition from BAP (BMP4, A83-01 and PD173074)-treated human embryonic stem cells (hESCs) and performed multiple gain- and loss-of-function tests of TEAD4, CDX2 or GATA3 to study their roles during this process. Although hESCs with TEAD4 deletion maintain pluripotency, their trophoblast transition potentials are attenuated. This impaired trophoblast transition could be rescued by separately overexpressingTEAD4,CDX2orGATA3. Furthermore, trophoblast transition from hESCs is also attenuated by knockout ofCDX2but remains unaffected with deletion ofGATA3. However,CDX2-overexpressed hESCs maintain pluripotency, whereas overexpression ofGATA3in hESCs leads to spontaneous differentiation including trophoblast lineage. In brief, our findings using a human model of trophoblast transition from BAP-treated hESCs reveal transcription roles ofTEAD4,CDX2andGATAin humans that are different from those in mice. We hope that this evidence can aid in understanding the distinct transcriptional network regulating trophoblast development in humans.