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Nature. 2016 Jan 21;529(7586):403-407. doi: 10.1038/nature16480. Epub 2016 Jan 11.

NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers.

Murakami K#1,2,3,4,5, Günesdogan U#1,2,3, Zylicz JJ1,2,3, Tang WWC1,2,3, Sengupta R1,2,3, Kobayashi T1,2,3, Kim S1,2,3, Butler R1, Dietmann S3, Surani MA1,2,3.

Author information

1
Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
2
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
3
Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
4
Laboratory for Pluripotent Cell Studies, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
5
Laboratory for Molecular and Cellular Biology, Faculty of Advanced Life Science, Hokkaido University, Kita21 Nishi11, Kita-ku, Sapporo, Hokkaido 001-0021, Japan.
#
Contributed equally

Abstract

Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice, where its precise role is yet unclear. 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 fate. 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 cells. 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 EpiLCs, 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.

PMID:
26751055
PMCID:
PMC4724940
DOI:
10.1038/nature16480
[Indexed for MEDLINE]
Free PMC Article

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