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

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. H...

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Veröffentlicht in:The EMBO journal 2015-06, Vol.34 (12), p.1630-1647
Hauptverfasser: Li, Tangliang, Shi, Yue, Wang, Pei, Guachalla, Luis Miguel, Sun, Baofa, Joerss, Tjard, Chen, Yu-Sheng, Groth, Marco, Krueger, Anja, Platzer, Matthias, Yang, Yun-Gui, Rudolph, Karl Lenhard, Wang, Zhao-Qi
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container_end_page 1647
container_issue 12
container_start_page 1630
container_title The EMBO journal
container_volume 34
creator Li, Tangliang
Shi, Yue
Wang, Pei
Guachalla, Luis Miguel
Sun, Baofa
Joerss, Tjard
Chen, Yu-Sheng
Groth, Marco
Krueger, Anja
Platzer, Matthias
Yang, Yun-Gui
Rudolph, Karl Lenhard
Wang, Zhao-Qi
description 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. Synopsis New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes. The RNA endonuclease Smg6 functions in telomere maintenance and nonsense‐mediated decay (NMD) in mouse ESCs and MEFs. Loss of Smg6 does not compromise the viability of ESCs and MEFs. Smg6 regulates ESC differentiation and somatic cellular reprograming via its NMD function, not telomere maintenance. Smg6 modulates ESC differentiation by controlling mRNA stability of pluripotency genes, for example, c‐Myc. The NMD pathway acts as a general RNA surveillance mechanism safeguarding the cell identity switch. Graphical Abstract New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes.
doi_str_mv 10.15252/embj.201489947
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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. Synopsis New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes. The RNA endonuclease Smg6 functions in telomere maintenance and nonsense‐mediated decay (NMD) in mouse ESCs and MEFs. Loss of Smg6 does not compromise the viability of ESCs and MEFs. Smg6 regulates ESC differentiation and somatic cellular reprograming via its NMD function, not telomere maintenance. Smg6 modulates ESC differentiation by controlling mRNA stability of pluripotency genes, for example, c‐Myc. The NMD pathway acts as a general RNA surveillance mechanism safeguarding the cell identity switch. Graphical Abstract New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.15252/embj.201489947</identifier><identifier>PMID: 25770585</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>London: Blackwell Publishing Ltd</publisher><subject>Animals ; Cell differentiation ; Cell Differentiation - genetics ; Cell Differentiation - physiology ; cell reprograming ; Cloning, Molecular ; Computational Biology ; Decay ; DNA Primers - genetics ; EMBO36 ; EMBO39 ; Embryonic Stem Cells - physiology ; ESC differentiation ; Gene Expression Regulation, Developmental - genetics ; Gene Expression Regulation, Developmental - physiology ; Genetics ; Histological Techniques ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Mice ; Mice, Knockout ; NMD ; Nonsense Mediated mRNA Decay - physiology ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Real-Time Polymerase Chain Reaction ; Ribonucleic acid ; RNA ; RNA, Small Interfering - genetics ; Rodents ; Sequence Analysis, RNA ; Smg6/Est1 ; Stem cells ; telomere</subject><ispartof>The EMBO journal, 2015-06, Vol.34 (12), p.1630-1647</ispartof><rights>The Authors. Published under the terms of the CC BY NC ND 4.0 license 2015</rights><rights>2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license</rights><rights>2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license.</rights><rights>2015 EMBO</rights><rights>2015 The Authors. 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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. Synopsis New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes. The RNA endonuclease Smg6 functions in telomere maintenance and nonsense‐mediated decay (NMD) in mouse ESCs and MEFs. Loss of Smg6 does not compromise the viability of ESCs and MEFs. Smg6 regulates ESC differentiation and somatic cellular reprograming via its NMD function, not telomere maintenance. Smg6 modulates ESC differentiation by controlling mRNA stability of pluripotency genes, for example, c‐Myc. The NMD pathway acts as a general RNA surveillance mechanism safeguarding the cell identity switch. 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Shi, Yue ; Wang, Pei ; Guachalla, Luis Miguel ; Sun, Baofa ; Joerss, Tjard ; Chen, Yu-Sheng ; Groth, Marco ; Krueger, Anja ; Platzer, Matthias ; Yang, Yun-Gui ; Rudolph, Karl Lenhard ; Wang, Zhao-Qi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6217-5c28a3b917a38b8bef3226f81134b12acdd2f3c1bc712bb21517f4b8ef80442e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Cell differentiation</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Differentiation - physiology</topic><topic>cell reprograming</topic><topic>Cloning, Molecular</topic><topic>Computational Biology</topic><topic>Decay</topic><topic>DNA Primers - genetics</topic><topic>EMBO36</topic><topic>EMBO39</topic><topic>Embryonic Stem Cells - physiology</topic><topic>ESC differentiation</topic><topic>Gene Expression Regulation, Developmental - genetics</topic><topic>Gene Expression Regulation, Developmental - physiology</topic><topic>Genetics</topic><topic>Histological Techniques</topic><topic>Immunoblotting</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>NMD</topic><topic>Nonsense Mediated mRNA Decay - physiology</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Small Interfering - genetics</topic><topic>Rodents</topic><topic>Sequence Analysis, RNA</topic><topic>Smg6/Est1</topic><topic>Stem cells</topic><topic>telomere</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Tangliang</creatorcontrib><creatorcontrib>Shi, Yue</creatorcontrib><creatorcontrib>Wang, Pei</creatorcontrib><creatorcontrib>Guachalla, Luis Miguel</creatorcontrib><creatorcontrib>Sun, Baofa</creatorcontrib><creatorcontrib>Joerss, Tjard</creatorcontrib><creatorcontrib>Chen, Yu-Sheng</creatorcontrib><creatorcontrib>Groth, Marco</creatorcontrib><creatorcontrib>Krueger, Anja</creatorcontrib><creatorcontrib>Platzer, Matthias</creatorcontrib><creatorcontrib>Yang, Yun-Gui</creatorcontrib><creatorcontrib>Rudolph, Karl Lenhard</creatorcontrib><creatorcontrib>Wang, Zhao-Qi</creatorcontrib><collection>Istex</collection><collection>Springer Nature OA Free Journals</collection><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; 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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. Synopsis New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes. The RNA endonuclease Smg6 functions in telomere maintenance and nonsense‐mediated decay (NMD) in mouse ESCs and MEFs. Loss of Smg6 does not compromise the viability of ESCs and MEFs. Smg6 regulates ESC differentiation and somatic cellular reprograming via its NMD function, not telomere maintenance. Smg6 modulates ESC differentiation by controlling mRNA stability of pluripotency genes, for example, c‐Myc. The NMD pathway acts as a general RNA surveillance mechanism safeguarding the cell identity switch. Graphical Abstract New genetic data show that the NMD pathway is dispensable for growth of embryonic stem cells (ESCs) but essential for differentiation and reprogramming via repression of key pluripotency genes.</abstract><cop>London</cop><pub>Blackwell Publishing Ltd</pub><pmid>25770585</pmid><doi>10.15252/embj.201489947</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
Cell differentiation
Cell Differentiation - genetics
Cell Differentiation - physiology
cell reprograming
Cloning, Molecular
Computational Biology
Decay
DNA Primers - genetics
EMBO36
EMBO39
Embryonic Stem Cells - physiology
ESC differentiation
Gene Expression Regulation, Developmental - genetics
Gene Expression Regulation, Developmental - physiology
Genetics
Histological Techniques
Immunoblotting
In Situ Hybridization, Fluorescence
Mice
Mice, Knockout
NMD
Nonsense Mediated mRNA Decay - physiology
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Real-Time Polymerase Chain Reaction
Ribonucleic acid
RNA
RNA, Small Interfering - genetics
Rodents
Sequence Analysis, RNA
Smg6/Est1
Stem cells
telomere
title Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay
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