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Smg6/Est1 licenses embryonic stem cell differentiation via nonsense‐mediated mRNA decay
Author(s) -
Li Tangliang,
Shi Yue,
Wang Pei,
Guachalla Luis Miguel,
Sun Baofa,
Joerss Tjard,
Chen YuSheng,
Groth Marco,
Krueger Anja,
Platzer Matthias,
Yang YunGui,
Rudolph Karl Lenhard,
Wang ZhaoQi
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489947
Subject(s) - biology , embryonic stem cell , nonsense mediated decay , microbiology and biotechnology , messenger rna , stem cell , genetics , rna , gene , rna splicing
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 ESC s 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 ( iPSC s). 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.