期刊
GENES & DEVELOPMENT
卷 32, 期 7-8, 页码 568-576出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.310086.117
关键词
2i; ERF; pluripotency; RAS; mESCs
资金
- La Caixa Foundation
- Boehringer Ingelheim Fonds
- Ramon y Cajal contract [RYC-2011-09242]
- Fundacion Botin
- Banco Santander through its Santander Universities Global Division
- Spanish Ministry of Economy and Competitiveness (European Fonds Europeen de Developpement Economique et Regional [FEDER] funds) [SAF2011-23753, SAF2014-57791-REDC]
- Fundacio La Marato de TV3
- Howard Hughes Medical Institute
- European Research Council [ERC617840]
- Spanish Ministry of Economy and Competitiveness (European FEDER funds) [SAF2013-49147-P, SAF2016-80874-P]
MEK inhibition in combination with a glycogen synthase kinase-3 beta (GSK3 beta) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.
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