The oncogene Etv5 promotes MET in somatic reprogramming and orchestrates epiblast/primitive endoderm specification during mESCs differentiation

Jinglong Zhang,Jing Xie,Huayan Wang,Chen Fan,Xin He,Hongxia Cao,Shiqiang Zhang,Mingzhi Liao,Youlong Xie

doi:10.1038/s41419-018-0335-1

Jinglong Zhang, Jing Xie + Show 7 more

Open Access

https://doi.org/10.1038/s41419-018-0335-1

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Abstract

Unipotent spermatogonial stem cells (SSCs) can be efficiently reprogrammed into pluripotent stem cells only by manipulating the culture condition, without introducing exogenous reprogramming factors. This phenotype raises the hypothesis that the endogenous transcription factors (TFs) in SSCs may facilitate reprogramming to acquire pluripotency. In this study, we screened a pool of SSCs TFs (Bcl6b, Lhx1, Foxo1, Plzf, Id4, Taf4b, and Etv5), and found that oncogene Etv5 could dramatically increase the efficiency of induced pluripotent stem cells (iPSCs) generation when combined with Yamanaka factors. We also demonstrated that Etv5 could promote mesenchymal-epithelial transition (MET) at the early stage of reprogramming by regulating Tet2-miR200s-Zeb1 axis. In addition, Etv5 knockdown in mouse embryonic stem cells (mESCs) could decrease the genomic 5hmC level by downregulating Tet2. Furthermore, the embryoid body assay revealed that Etv5 could positively regulate primitive endoderm specification through regulating Gata6 and negatively regulate epiblast specification by inhibiting Fgf5 expression. In summary, our findings provide insights into understanding the regulation mechanisms of Etv5 under the context of somatic reprogramming, mESCs maintenance, and differentiation.

Highlights

Somatic cells can be reprogrammed into pluripotent state by overexpressing defined transcription factors (TFs) in vitro[1]
TFs could promote the efficiency of generating induced pluripotent stem cells (Fig. 1a)
We demonstrated that the downregulation of Tet[2] and Gata[6] in Etv5-KD mouse embryonic stem cells (mESCs) was recovered as Etv[5] was reintroduced (Fig. 6a)

Summary

Introduction

Somatic cells can be reprogrammed into pluripotent state by overexpressing defined transcription factors (TFs) in vitro[1]. SSCs can be efficiently reprogrammed into pluripotent state only by changing the culture condition without overexpressing exogenous TFs3. These evidences indicate the TFs involved in SSCs self-renewal may facilitate the. Etv[5] is suggested to regulate proliferation and differentiation of mouse embryonic stem cells (mESCs)[6]. Etv[5] has been found as an early regulator during somatic reprogramming[7]. The exact mechanism of Etv[5] in mESCs and somatic reprogramming remains unclear

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