Transcription coactivator Cited1 acts as an inducer of trophoblast-like state from mouse embryonic stem cells through the activation of BMP signaling

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Bone Morphogenetic Protein 1 / metabolism*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Cell Line
  • E1A-Associated p300 Protein / metabolism
  • Female
  • Gene Expression Regulation, Developmental / genetics*
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Placenta / embryology
  • Pregnancy
  • Signal Transduction
  • Smad4 Protein / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription, Genetic / genetics
  • Trophoblasts / cytology*


  • Apoptosis Regulatory Proteins
  • Cited1 protein, mouse
  • Nuclear Proteins
  • Smad4 Protein
  • Smad4 protein, mouse
  • Trans-Activators
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II
  • Bmp1 protein, mouse
  • Bone Morphogenetic Protein 1