title: Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay.
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.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Tangliang
authors.initials: T
authors.lastname: Li
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Guachalla
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Baofa
authors.initials: B
authors.lastname: Sun
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Tjard
authors.initials: T
authors.lastname: Joerss
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Groth
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Krueger
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.affiliation: Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: 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.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006652:Histological Techniques; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D059365:Nonsense Mediated mRNA Decay / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases; C551743:Smg1 protein, mouse
keywords: ESC differentiation; NMD; Smg6/Est1; cell reprograming; telomere