Basic Clinical Research Center, Renji Hospital, Department of Histology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, 200025, Shanghai, China.
KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Herestraat 49, 3000, Leuven, Belgium.
Cell Death Dis. 2018 Sep 11;9(9):924. doi: 10.1038/s41419-018-0991-1.
Trophoblast lineages, precursors of the placenta, are essential for post-implantation embryo survival. However, the regulatory network of trophoblast development remains incompletely understood. Here, we report that Cited1, a transcription coactivator, is a robust inducer for trophoblast-like state from mouse embryonic stem cells (ESCs). Depletion of Cited1 in ESCs compromises the trophoblast lineage specification induced by BMP signaling. In contrast, overexpression of Cited1 in ESCs induces a trophoblast-like state with elevated expression of trophoblast marker genes in vitro and generation of trophoblastic tumors in vivo. Furthermore, global transcriptome profile analysis indicates that ectopic Cited1 activates a trophoblast-like transcriptional program in ESCs. Mechanistically, Cited1 interacts with Bmpr2 and Smad4 to activate the Cited1-Bmpr2-Smad1/5/8 axis in the cytoplasm and Cited1-Smad4-p300 complexes in the nucleus, respectively. Collectively, our results show that Cited1 plays an important role in regulating trophoblast lineage specification through activating the BMP signaling pathway.
滋养层谱系是胎盘的前体，对于着床后胚胎的存活至关重要。然而，滋养层发育的调控网络仍不完全清楚。在这里，我们报告 Cited1，一种转录共激活因子，是诱导小鼠胚胎干细胞（ESC）向滋养层样状态的有力诱导剂。ESC 中 Cited1 的缺失会损害 BMP 信号诱导的滋养层谱系特化。相比之下，ESC 中 Cited1 的过表达在体外诱导出滋养层样状态，并在体内产生滋养层肿瘤。此外，全转录组谱分析表明，异位 Cited1 在 ESC 中激活了一种滋养层样的转录程序。在机制上，Cited1 与 Bmpr2 和 Smad4 相互作用，分别在细胞质中激活 Cited1-Bmpr2-Smad1/5/8 轴，在核内激活 Cited1-Smad4-p300 复合物。总之，我们的研究结果表明，Cited1 通过激活 BMP 信号通路在调节滋养层谱系特化中发挥重要作用。
