Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice1, where its precise role is yet unclear2,3,4. We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate5. Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells6,7,8. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs9,10, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.
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Gene Expression Omnibus
Microarray data have been deposited in the Gene Expression Omnibus under accession number GSE71933.
We thank H. Leitch for ES cell lines, C. Lee for help with animal husbandry, H. Niwa for vectors and conditional Sox2-knockout ES cells, N. Miller, R. Walker and A. Riddell for FACS sorting and J. Bauer for analysis of microarray data. K.M. was supported by the Japan Society for the Promotion of Science (JSPS) Institutional Program for Young Researchers Overseas Visits. U.G. was supported by a Marie Skłodowska-Curie and a Newton Trust/Leverhulme Trust Early Career fellowship. J.J.Z. was a recipient of a Wellcome Trust PhD Studentship (RG44593). T.K. was supported by a JSPS Fellowship for research abroad. This research was supported by Gurdon Institute core grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492), and a grant from the Wellcome Trust to M.A.S. (WT096738).
Extended data figures
This table contains oligonucleotide sequences.
About this article
The EMBO Journal (2019)