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EMBO J. 2015 Jun 12;34(12):1630-47. doi: 10.15252/embj.201489947. Epub 2015 Mar 14.

Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay.

Author information

1
Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
2
Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
3
Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany.
4
Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany.
5
Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany Faculty of Biology and Pharmacy, Friedrich-Schiller University of Jena, Jena, Germany zqwang@fli-leibniz.de.

Abstract

Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.

KEYWORDS:

ESC differentiation; NMD; Smg6/Est1; cell reprograming; telomere

PMID:
25770585
PMCID:
PMC4475398
DOI:
10.15252/embj.201489947
[Indexed for MEDLINE]
Free PMC Article

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