@article{f4c7ee5a56de4dd0a328ae99d6990d0a,
title = "Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency",
abstract = "The gene regulatory network (GRN)of naive mouse embryonic stem cells (ESCs)must be reconfigured to enable lineage commitment. TCF3 sanctions rewiring by suppressing components of the ESC transcription factor circuitry. However, TCF3 depletion only delays and does not prevent transition to formative pluripotency. Here, we delineate additional contributions of the ETS-family transcription factor ETV5 and the repressor RBPJ. In response to ERK signaling, ETV5 switches activity from supporting self-renewal and undergoes genome relocation linked to commissioning of enhancers activated in formative epiblast. Independent upregulation of RBPJ prevents re-expression of potent naive factors, TBX3 and NANOG, to secure exit from the naive state. Triple deletion of Etv5, Rbpj, and Tcf3 disables ESCs, such that they remain largely undifferentiated and locked in self-renewal, even in the presence of differentiation stimuli. Thus, genetic elimination of three complementary drivers of network transition stalls developmental progression, emulating environmental insulation by small-molecule inhibitors.",
keywords = "commitment, differentiation, embryonic stem cell, epiblast, ETS factors, gene regulatory network, pluripotency, RBPJ, self-renewal",
author = "T{\"u}zer Kalkan and Susanne Bornel{\"o}v and Carla Mulas and Evangelia Diamanti and Tim Lohoff and Meryem Ralser and Sjors Middelkamp and Patrick Lombard and Jennifer Nichols and Austin Smith",
note = "Funding Information: We are grateful to Maike Paramor for preparing libraries, Rosalind Drummond for technical assistance, Ken Jones for providing the H2B-tdTomato construct, Peter Humphreys for imaging support, and James Clarke for lab management. We thank Andrew Sharrocks for discussion, Frank Costantini for providing Etv4/Etv5 double-mutant ESCs, and Hendrik Marks and Henk Stunnenberg for H3K4me3 ChIP-seq. This research was funded by the Wellcome Trust , the Biotechnology and Biological Sciences Research Council , European Commission (FP7 contract no. 200720 , EuroSyStem), the Leverhulme Trust , and the Louis Jeantet Foundation . The Cambridge Stem Cell Institute receives core support from the Wellcome Trust and the Medical Research Council . A.S. is a Medical Research Council Professor. Funding Information: We are grateful to Maike Paramor for preparing libraries, Rosalind Drummond for technical assistance, Ken Jones for providing the H2B-tdTomato construct, Peter Humphreys for imaging support, and James Clarke for lab management. We thank Andrew Sharrocks for discussion, Frank Costantini for providing Etv4/Etv5 double-mutant ESCs, and Hendrik Marks and Henk Stunnenberg for H3K4me3 ChIP-seq. This research was funded by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council, European Commission (FP7 contract no. 200720, EuroSyStem), the Leverhulme Trust, and the Louis Jeantet Foundation. The Cambridge Stem Cell Institute receives core support from the Wellcome Trust and the Medical Research Council. A.S. is a Medical Research Council Professor. Conceptualization, T.K. and A.S.; Methodology, T.K.; Formal Analysis, T.K. S.B. E.D. M.R. and P.L.; Investigation, T.K. C.M. T.L. S.M. and J.N.; Writing, T.K. and A.S.; Supervision, J.N. and A.S. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = may,
day = "2",
doi = "10.1016/j.stem.2019.03.017",
language = "English",
volume = "24",
pages = "785--801.e7",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Elsevier",
number = "5",
}