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

Francesco Cambuli, Alexander Murray, Wendy Dean, Dominika Dudzinska, Felix Krueger, Simon Andrews, Claire E. Senner, Simon J. Cook and Myriam Hemberger ()
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Francesco Cambuli: Epigenetics Programme, The Babraham Institute
Alexander Murray: Epigenetics Programme, The Babraham Institute
Wendy Dean: Epigenetics Programme, The Babraham Institute
Dominika Dudzinska: Epigenetics Programme, The Babraham Institute
Felix Krueger: Bioinformatics Group, The Babraham Institute
Simon Andrews: Bioinformatics Group, The Babraham Institute
Claire E. Senner: Epigenetics Programme, The Babraham Institute
Simon J. Cook: Signalling Programme, The Babraham Institute
Myriam Hemberger: Epigenetics Programme, The Babraham Institute

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6538

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