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

Abstract

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.

Single‐cell RNA sequencing reveals the landscape of early female germ cell development

“…30 Moreover, various TF cofactors including Cited1, Nfkbia, and Lmo4 were also identified in FGCs ( Figure 3A), and these cofactors could interact with numerous TFs that are highly expressed in FGCs to regulate early oogenesis. [31][32][33] Dynamic cell cycle regulation is crucial for FGC development. Our data indicated that the cell cycle genes in meiocytes underwent complex regulations and they were very different compared to those in somatic cells.…”

CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

“…Unlike Cited2, both Cited1 and Cited4 are poorly expressed in undifferentiated ESC and might not play a major role in the maintenance of the pluripotency [43,46]. Moreover, Cited1 overexpression in mouse ESC triggers their transition to a trophoblast-like state by activation of a trophoblast transcriptional program [43]. In undifferentiated mouse ESC, Cited2 directly controls the expression of Nanog, Tbx3 and Klf4 transcripts and the promoter activity of these genes (Figures 1 and 2, and Table 1), and in turn, Nanog activates Cited2 promoter activity [38].…”

“…Conversely, Cited2 acute depletion not only impairs proliferation, but also triggers cell death by apoptosis and spontaneous differentiation of ESC [38]. Unlike Cited2, both Cited1 and Cited4 are poorly expressed in undifferentiated ESC and might not play a major role in the maintenance of the pluripotency [43,46]. Moreover, Cited1 overexpression in mouse ESC triggers their transition to a trophoblast-like state by activation of a trophoblast transcriptional program [43].…”

“…Interestingly, hypoxic treatment of mouse "naïve" ESC, or HIF-1ɑ stabilization in these cells, decrease their proliferation rate and drives them to transition from a "naïve" to a "primed" pluripotent state [121][122][123] In early mouse development, Cited1 protein is expressed from 2-cell to blastocyst stages and localizes primarily in the cytoplasm [43]. In blastocysts, Cited1 is mostly detected in the extraembryonic trophectoderm, and its expression in blastocyst structures is inversely correlated to Oct4 expression and activated by BMP4 [43]. These observations are in agreement with the major role played by Cited1 in placental development [9].…”

“…Several reports have now pointed out the expression and the role of CITED proteins in stem cells (including ESC), in which they are involved in selfrenewal and cell fate decisions [38,[41][42][43][44][45][46]. Not surprisingly, due to the plethora of cellular and embryonic functions exerted by CITED1, CITED2 and CITED4, these genes were also showed to play intricate roles in tumorigenic processes [5,45,[47][48][49][50][51][52][53][54][55][56][57][58][59].…”