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

By M. Stadtfeld, E. Apostolou, H. Akutsu, A. Fukuda, Patricia Follett, S. Natesan, T. Kono, T. Shioda, K. Hochedlinger. Nature, 2010

790 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/add5144052822eb680f4e300c21ccc52d4626501

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Citations in the corpus

Induced pluripotency: history, mechanisms, and applications. (2010, background): “…formed teratomas and contributed to low-grade chimeras, only cells with an ESC-equivalent expression pattern of Dlk1–Dio3 had the capacity to contribute to high-grade chimeras and form viable ‘‘all-iPSC’’ mice after injection into tetraploid blastocysts (L Liu et al. 2010; Stadtfeld et al. 2010b).”
Somatic cell reprogramming and transitions between pluripotent states: facts, hypotheses, unresolved issues (2010, neutral): “Abnormal expression of this cluster was not observed in human iPSCs (Stadtfeld et al., 2010).”
Epigenetic memory in induced pluripotent stem cells (2010, background): “The Dlk1-Dio3 locus, whose expression correlates with capacity to generate “all-iPSC” mice 44 , is not differentially methylated and expressed in at least some iPSC lines that manifest epigenetic memory (our unpublished observations).”
Emerging trends in regenerative medicine: a scientometric analysis in CiteSpace (2012, background): “Although iPSCs resemble embryonic stem cells (ESCs) inmany ways, comparative studies have found potentially profound differences [4-6].”
Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines (2011, positive): “Several gene signatures of differences between human ES and iPS cell lines have been reported in the literature (Chin et al., 2009; Doi et al., 2009; Stadtfeld et al., 2010).”
Control of Embryonic Stem Cell State (2011, background): “In one study with genetically matched murine ESCs and iPSCs, no consistent gene expression differences were observed, except for transcripts within the imprinted Dlk1–Dio3 gene cluster (Stadtfeld et al., 2010).”
Induced pluripotent stem cells: past, present, and future. (2012, positive): “We learned an important lesson from two related reports regarding mouse iPSCs (Carey et al., 2011; Stadtfeld et al., 2010).”
The tumorigenicity of human embryonic and induced pluripotent stem cells (2011, background): “Recent studies found variability in the expression of imprinted genes among different lines of both mouse and human iPSC”
The promise of induced pluripotent stem cells in research and therapy (2012, methodology): “This test has been accomplished for only a limited subset of iPS cell”
X-inactivation, imprinting, and long noncoding RNAs in health and disease. (2013, background): “One study found that mouse iPSC clones with aberrant Dlk1-Dio3 imprinting and low Gtl2 expression contributed poorly to chimeras (Stadtfeld et al., 2010), whereas another did not observe a difference (Carey et al., 2011).”