title: Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast.
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.
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cambuli
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Murray
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Dominika
authors.initials: D
authors.lastname: Dudzinska
authors.affiliation: Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Felix
authors.initials: F
authors.lastname: Krueger
authors.affiliation: Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Andrews
authors.affiliation: 1] Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK [2] Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Senner
authors.affiliation: Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.affiliation: 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.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D065150:Cellular Reprogramming; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D050814:Octamer Transcription Factor-3; D014157:Transcription Factors