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Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells

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  • Matthias Stadtfeld

    (Howard Hughes Medical Institute at Massachusetts General Hospital, Center for Regenerative Medicine; Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Harvard University and Harvard Medical School, 42 Church Street, Cambridge, Massachusetts 02138, USA)

  • Effie Apostolou

    (Howard Hughes Medical Institute at Massachusetts General Hospital, Center for Regenerative Medicine; Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Harvard University and Harvard Medical School, 42 Church Street, Cambridge, Massachusetts 02138, USA)

  • Hidenori Akutsu

    (National Institute for Child Health and Development)

  • Atsushi Fukuda

    (Tokyo University of Agriculture)

  • Patricia Follett

    (Howard Hughes Medical Institute at Massachusetts General Hospital, Center for Regenerative Medicine; Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA)

  • Sridaran Natesan

    (Sanofi-Aventis, 270 Albany Street, Cambridge, Massachusetts 02139, USA)

  • Tomohiro Kono

    (Tokyo University of Agriculture)

  • Toshi Shioda

    (Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA)

  • Konrad Hochedlinger

    (Howard Hughes Medical Institute at Massachusetts General Hospital, Center for Regenerative Medicine; Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Harvard Stem Cell Institute, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Harvard University and Harvard Medical School, 42 Church Street, Cambridge, Massachusetts 02138, USA)

Abstract

Induced pluripotent stem cells (iPSCs) have been generated by enforced expression of defined sets of transcription factors in somatic cells. It remains controversial whether iPSCs are molecularly and functionally equivalent to blastocyst-derived embryonic stem (ES) cells. By comparing genetically identical mouse ES cells and iPSCs, we show here that their overall messenger RNA and microRNA expression patterns are indistinguishable with the exception of a few transcripts encoded within the imprinted Dlk1–Dio3 gene cluster on chromosome 12qF1, which were aberrantly silenced in most of the iPSC clones. Consistent with a developmental role of the Dlk1–Dio3 gene cluster, these iPSC clones contributed poorly to chimaeras and failed to support the development of entirely iPSC-derived animals (‘all-iPSC mice’). In contrast, iPSC clones with normal expression of the Dlk1–Dio3 cluster contributed to high-grade chimaeras and generated viable all-iPSC mice. Notably, treatment of an iPSC clone that had silenced Dlk1–Dio3 with a histone deacetylase inhibitor reactivated the locus and rescued its ability to support full-term development of all-iPSC mice. Thus, the expression state of a single imprinted gene cluster seems to distinguish most murine iPSCs from ES cells and allows for the prospective identification of iPSC clones that have the full development potential of ES cells.

Suggested Citation

  • Matthias Stadtfeld & Effie Apostolou & Hidenori Akutsu & Atsushi Fukuda & Patricia Follett & Sridaran Natesan & Tomohiro Kono & Toshi Shioda & Konrad Hochedlinger, 2010. "Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells," Nature, Nature, vol. 465(7295), pages 175-181, May.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7295:d:10.1038_nature09017
    DOI: 10.1038/nature09017
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    Cited by:

    1. Maria Arez & Melanie Eckersley-Maslin & Tajda Klobučar & João Gilsa Lopes & Felix Krueger & Annalisa Mupo & Ana Cláudia Raposo & David Oxley & Samantha Mancino & Anne-Valerie Gendrel & Bruno Bernardes, 2022. "Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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