Transcription Coactivator Cited1 Acts As An Inducer Of Trophoblast-like State From Mouse Embryonic Stem Cells Through The Activation Of BMP Signaling

Trophoblast lineages,as precursors of the placenta,are essential for post-implantation embryo survival.However,the regulatory networks for trophoblast development remain 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 dramatically attenuates 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 both Bmpr2 and Smad4 to activate the Cited1-Bmpr2-Smad1/5/8 axis in the cytoplasm and Cited1-Smad4-p300 complex in the nucleus.Collectively,our results show that Cited1 plays an important role in regulating trophoblast lineage specification through activating the BMP signaling pathway.