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Nat Commun. 2014 Nov 26;5:5538. doi: 10.1038/ncomms6538.

Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast.

Author information

1
1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
2
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
3
Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
4
Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
5
1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK [3] Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Tennis Court Road, Cambridge CB2 1QR, UK.

Abstract

Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Nonetheless, ES cells can seemingly acquire TS-like characteristics upon manipulation of lineage-determining transcription factors or activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Here we have interrogated the progression of reprogramming in ES cell models with regulatable Oct4 and Cdx2 transgenes or conditional Erk1/2 activation. Although trans-differentiation into TS-like cells is initiated, lineage conversion remains incomplete in all models, underpinned by the failure to demethylate a small group of TS cell genes. Forced expression of these non-reprogrammed genes improves trans-differentiation efficiency, but still fails to confer a stable TS cell phenotype. Thus, even ES cells in ground-state pluripotency cannot fully overcome the boundaries that separate the first cell lineages but retain an epigenetic memory of their ES cell origin.

PMID:
25423963
PMCID:
PMC4263130
DOI:
10.1038/ncomms6538
[Indexed for MEDLINE]
Free PMC Article

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