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

Matthias Stadtfeld, Effie Apostolou, Hidenori Akutsu, Atsushi Fukuda, Patricia Follett, Sridaran Natesan, Tomohiro Kono, Toshi Shioda and Konrad Hochedlinger ()
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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
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
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
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

Nature, 2010, vol. 465, issue 7295, 175-181

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09017

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