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...
Gespeichert in:
Veröffentlicht in: | The EMBO journal 2015-06, Vol.34 (12), p.1630-1647 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
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 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4475398</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1688005888</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6217-5c28a3b917a38b8bef3226f81134b12acdd2f3c1bc712bb21517f4b8ef80442e3</originalsourceid><addsrcrecordid>eNqFkt1vFCEUxYnR2LX67Jsh8cWX6XIZGBgfTOpmu2raarSmjwQYZmWdjwqz1f3vZZy6WU2MCQkEfudwLheEngI5AU45nbvWbE4oASbLkol7aAasIBklgt9HM0ILyBjI8gg9inFDCOFSwEN0RLkQac1n6PpTuy7myzgAbrx1XXQRJ8-w6ztvcRxci61rGlz5unbBdYPXg-87fOs17vqEp5G1rkrbrsLtx8tTXDmrd4_Rg1o30T25m4_R57Pl1eJNdv5-9XZxep7ZgoLIuKVS56YEoXNppHF1TmlRS4CcGaDaVhWtcwvGCqDGUOAgamakqyVhjLr8GL2afG-2JsVIFQxBN-om-FaHneq1V3-edP6LWve3ijHB81Imgxd3BqH_tnVxUK2PY8m6c_02KiikHN9Njujzv9BNvw1dKm-khCRQUpGo-UTZ0McYXL0PA0T9apoam6b2TUuKZ4c17PnfXUrAywn47hu3-5-fWl68fnfoTiZxTLpu7cJB6n8GyiaJTx_gx_4-Hb6qQuSCq-vLlRKLD1cXq7OFYvlPO9PDbQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1687801927</pqid></control><display><type>article</type><title>Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><source>Springer Nature OA Free Journals</source><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</creator><creatorcontrib>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</creatorcontrib><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.</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. Published under the terms of the CC BY NC ND 4.0 license 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6217-5c28a3b917a38b8bef3226f81134b12acdd2f3c1bc712bb21517f4b8ef80442e3</citedby><cites>FETCH-LOGICAL-c6217-5c28a3b917a38b8bef3226f81134b12acdd2f3c1bc712bb21517f4b8ef80442e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475398/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475398/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27903,27904,41099,42168,45553,45554,46387,46811,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25770585$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><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><title>Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><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.</description><subject>Animals</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - physiology</subject><subject>cell reprograming</subject><subject>Cloning, Molecular</subject><subject>Computational Biology</subject><subject>Decay</subject><subject>DNA Primers - genetics</subject><subject>EMBO36</subject><subject>EMBO39</subject><subject>Embryonic Stem Cells - physiology</subject><subject>ESC differentiation</subject><subject>Gene Expression Regulation, Developmental - genetics</subject><subject>Gene Expression Regulation, Developmental - physiology</subject><subject>Genetics</subject><subject>Histological Techniques</subject><subject>Immunoblotting</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>NMD</subject><subject>Nonsense Mediated mRNA Decay - physiology</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Small Interfering - genetics</subject><subject>Rodents</subject><subject>Sequence Analysis, RNA</subject><subject>Smg6/Est1</subject><subject>Stem cells</subject><subject>telomere</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkt1vFCEUxYnR2LX67Jsh8cWX6XIZGBgfTOpmu2raarSmjwQYZmWdjwqz1f3vZZy6WU2MCQkEfudwLheEngI5AU45nbvWbE4oASbLkol7aAasIBklgt9HM0ILyBjI8gg9inFDCOFSwEN0RLkQac1n6PpTuy7myzgAbrx1XXQRJ8-w6ztvcRxci61rGlz5unbBdYPXg-87fOs17vqEp5G1rkrbrsLtx8tTXDmrd4_Rg1o30T25m4_R57Pl1eJNdv5-9XZxep7ZgoLIuKVS56YEoXNppHF1TmlRS4CcGaDaVhWtcwvGCqDGUOAgamakqyVhjLr8GL2afG-2JsVIFQxBN-om-FaHneq1V3-edP6LWve3ijHB81Imgxd3BqH_tnVxUK2PY8m6c_02KiikHN9Njujzv9BNvw1dKm-khCRQUpGo-UTZ0McYXL0PA0T9apoam6b2TUuKZ4c17PnfXUrAywn47hu3-5-fWl68fnfoTiZxTLpu7cJB6n8GyiaJTx_gx_4-Hb6qQuSCq-vLlRKLD1cXq7OFYvlPO9PDbQ</recordid><startdate>20150612</startdate><enddate>20150612</enddate><creator>Li, Tangliang</creator><creator>Shi, Yue</creator><creator>Wang, Pei</creator><creator>Guachalla, Luis Miguel</creator><creator>Sun, Baofa</creator><creator>Joerss, Tjard</creator><creator>Chen, Yu-Sheng</creator><creator>Groth, Marco</creator><creator>Krueger, Anja</creator><creator>Platzer, Matthias</creator><creator>Yang, Yun-Gui</creator><creator>Rudolph, Karl Lenhard</creator><creator>Wang, Zhao-Qi</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group UK</general><general>BlackWell Publishing Ltd</general><scope>BSCLL</scope><scope>C6C</scope><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150612</creationdate><title>Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay</title><author>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</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 & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Tangliang</au><au>Shi, Yue</au><au>Wang, Pei</au><au>Guachalla, Luis Miguel</au><au>Sun, Baofa</au><au>Joerss, Tjard</au><au>Chen, Yu-Sheng</au><au>Groth, Marco</au><au>Krueger, Anja</au><au>Platzer, Matthias</au><au>Yang, Yun-Gui</au><au>Rudolph, Karl Lenhard</au><au>Wang, Zhao-Qi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2015-06-12</date><risdate>2015</risdate><volume>34</volume><issue>12</issue><spage>1630</spage><epage>1647</epage><pages>1630-1647</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><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.
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> |
fulltext | fulltext |
identifier | ISSN: 0261-4189 |
ispartof | The EMBO journal, 2015-06, Vol.34 (12), p.1630-1647 |
issn | 0261-4189 1460-2075 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4475398 |
source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Springer Nature OA Free Journals |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T03%3A38%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Smg6/Est1%20licenses%20embryonic%20stem%20cell%20differentiation%20via%20nonsense-mediated%20mRNA%20decay&rft.jtitle=The%20EMBO%20journal&rft.au=Li,%20Tangliang&rft.date=2015-06-12&rft.volume=34&rft.issue=12&rft.spage=1630&rft.epage=1647&rft.pages=1630-1647&rft.issn=0261-4189&rft.eissn=1460-2075&rft.coden=EMJODG&rft_id=info:doi/10.15252/embj.201489947&rft_dat=%3Cproquest_pubme%3E1688005888%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1687801927&rft_id=info:pmid/25770585&rfr_iscdi=true |