Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression
Maintenance of pluripotency and specification towards a new cell fate are both dependent on precise interactions between extrinsic signals and transcriptional and epigenetic regulators. Directed methylation of cytosines by the methyltransferases DNMT3A and DNMT3B plays an important role in facilitat...
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| Veröffentlicht in: | Development (Cambridge) 2019-09, Vol.146 (19) |
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| creator | Tsankov, Alexander M Wadsworth, 2nd, Marc H Akopian, Veronika Charlton, Jocelyn Allon, Samuel J Arczewska, Aleksandra Mead, Benjamin E Drake, Riley S Smith, Zachary D Mikkelsen, Tarjei S Shalek, Alex K Meissner, Alexander |
| description | Maintenance of pluripotency and specification towards a new cell fate are both dependent on precise interactions between extrinsic signals and transcriptional and epigenetic regulators. Directed methylation of cytosines by the
methyltransferases DNMT3A and DNMT3B plays an important role in facilitating proper differentiation, whereas DNMT1 is essential for maintaining global methylation levels in all cell types. Here, we generated single-cell mRNA expression data from wild-type, DNMT3A, DNMT3A/3B and DNMT1 knockout human embryonic stem cells and observed a widespread increase in cellular and transcriptional variability, even with limited changes in global methylation levels in the
knockouts. Furthermore, we found unexpected transcriptional repression upon either loss of the
methyltransferase DNMT3A or the double knockout of DNMT3A/3B that is further propagated upon differentiation to mesoderm and ectoderm. Taken together, our single-cell RNA-sequencing data provide a high-resolution view into the consequences of depleting the three catalytically active DNMTs in human pluripotent stem cells. |
| doi_str_mv | 10.1242/dev.174722 |
| format | Article |
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methyltransferases DNMT3A and DNMT3B plays an important role in facilitating proper differentiation, whereas DNMT1 is essential for maintaining global methylation levels in all cell types. Here, we generated single-cell mRNA expression data from wild-type, DNMT3A, DNMT3A/3B and DNMT1 knockout human embryonic stem cells and observed a widespread increase in cellular and transcriptional variability, even with limited changes in global methylation levels in the
knockouts. Furthermore, we found unexpected transcriptional repression upon either loss of the
methyltransferase DNMT3A or the double knockout of DNMT3A/3B that is further propagated upon differentiation to mesoderm and ectoderm. Taken together, our single-cell RNA-sequencing data provide a high-resolution view into the consequences of depleting the three catalytically active DNMTs in human pluripotent stem cells.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.174722</identifier><identifier>PMID: 31515224</identifier><language>eng</language><publisher>England: The Company of Biologists Ltd</publisher><subject>Cell Cycle - genetics ; Cell Differentiation - genetics ; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism ; DNA (Cytosine-5-)-Methyltransferases - metabolism ; DNA Methylation - genetics ; DNA Methyltransferase 3A ; DNA Methyltransferase 3B ; Enhancer Elements, Genetic - genetics ; Entropy ; Gene Expression Regulation, Developmental ; Human Embryonic Stem Cells - metabolism ; Humans ; Male ; Repressor Proteins - metabolism ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Stem Cells and Regeneration ; Transcription, Genetic</subject><ispartof>Development (Cambridge), 2019-09, Vol.146 (19)</ispartof><rights>2019. Published by The Company of Biologists Ltd.</rights><rights>2019. Published by The Company of Biologists Ltd 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-faa73b0b517e311ecfe964042c3e7c734e5352abd2b1dac8d38337c09b090c673</citedby><cites>FETCH-LOGICAL-c378t-faa73b0b517e311ecfe964042c3e7c734e5352abd2b1dac8d38337c09b090c673</cites><orcidid>0000-0002-7955-4414 ; 0000-0001-8646-7469 ; 0000-0001-5670-8778</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3665,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31515224$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsankov, Alexander M</creatorcontrib><creatorcontrib>Wadsworth, 2nd, Marc H</creatorcontrib><creatorcontrib>Akopian, Veronika</creatorcontrib><creatorcontrib>Charlton, Jocelyn</creatorcontrib><creatorcontrib>Allon, Samuel J</creatorcontrib><creatorcontrib>Arczewska, Aleksandra</creatorcontrib><creatorcontrib>Mead, Benjamin E</creatorcontrib><creatorcontrib>Drake, Riley S</creatorcontrib><creatorcontrib>Smith, Zachary D</creatorcontrib><creatorcontrib>Mikkelsen, Tarjei S</creatorcontrib><creatorcontrib>Shalek, Alex K</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><title>Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression</title><title>Development (Cambridge)</title><addtitle>Development</addtitle><description>Maintenance of pluripotency and specification towards a new cell fate are both dependent on precise interactions between extrinsic signals and transcriptional and epigenetic regulators. Directed methylation of cytosines by the
methyltransferases DNMT3A and DNMT3B plays an important role in facilitating proper differentiation, whereas DNMT1 is essential for maintaining global methylation levels in all cell types. Here, we generated single-cell mRNA expression data from wild-type, DNMT3A, DNMT3A/3B and DNMT1 knockout human embryonic stem cells and observed a widespread increase in cellular and transcriptional variability, even with limited changes in global methylation levels in the
knockouts. Furthermore, we found unexpected transcriptional repression upon either loss of the
methyltransferase DNMT3A or the double knockout of DNMT3A/3B that is further propagated upon differentiation to mesoderm and ectoderm. Taken together, our single-cell RNA-sequencing data provide a high-resolution view into the consequences of depleting the three catalytically active DNMTs in human pluripotent stem cells.</description><subject>Cell Cycle - genetics</subject><subject>Cell Differentiation - genetics</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Methylation - genetics</subject><subject>DNA Methyltransferase 3A</subject><subject>DNA Methyltransferase 3B</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Entropy</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Human Embryonic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Stem Cells and Regeneration</subject><subject>Transcription, Genetic</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctOwzAQRS0EoqWw4QOQlwgpxY8krjdIVSkPqYIFsLYcZ9IapUmw00r9An4bpy0VbGxZc31m7lyELikZUhaz2xzWQypiwdgR6tNYiEhSJo9Rn8iERFRK2kNn3n8SQngqxCnqcZrQhLG4j75ntfe4LvD9yxgvoV1sytbpyhfgtAesTWvXtt1gW-HG2SXkeLFa6gpP37CBsvS4dXY-B-eDwjgIf_JtIeoOvNbO6syWHUFXOd6ijbNNa-tKl9hB48D78DhHJ4UuPVzs7wH6eJi-T56i2evj82Q8iwwXozYqtBY8I1lCBXBKwRQg05jEzHAQRvAYEp4wneUso7k2o5yPOBeGyIxIYlLBB-hux21WWXBjoAozlarzpt1G1dqq_5XKLtS8Xqt0RAKpA1zvAa7-WoFv1dL6zqyuoF55xZgMrRJGaJDe7KTGhSU7KA5tKFFdciokp3bJBfHV38EO0t-o-A9g0Jh5</recordid><startdate>20190912</startdate><enddate>20190912</enddate><creator>Tsankov, Alexander M</creator><creator>Wadsworth, 2nd, Marc H</creator><creator>Akopian, Veronika</creator><creator>Charlton, Jocelyn</creator><creator>Allon, Samuel J</creator><creator>Arczewska, Aleksandra</creator><creator>Mead, Benjamin E</creator><creator>Drake, Riley S</creator><creator>Smith, Zachary D</creator><creator>Mikkelsen, Tarjei S</creator><creator>Shalek, Alex K</creator><creator>Meissner, Alexander</creator><general>The Company of Biologists Ltd</general><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7955-4414</orcidid><orcidid>https://orcid.org/0000-0001-8646-7469</orcidid><orcidid>https://orcid.org/0000-0001-5670-8778</orcidid></search><sort><creationdate>20190912</creationdate><title>Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression</title><author>Tsankov, Alexander M ; Wadsworth, 2nd, Marc H ; Akopian, Veronika ; Charlton, Jocelyn ; Allon, Samuel J ; Arczewska, Aleksandra ; Mead, Benjamin E ; Drake, Riley S ; Smith, Zachary D ; Mikkelsen, Tarjei S ; Shalek, Alex K ; Meissner, Alexander</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-faa73b0b517e311ecfe964042c3e7c734e5352abd2b1dac8d38337c09b090c673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Cell Cycle - genetics</topic><topic>Cell Differentiation - genetics</topic><topic>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</topic><topic>DNA (Cytosine-5-)-Methyltransferases - metabolism</topic><topic>DNA Methylation - genetics</topic><topic>DNA Methyltransferase 3A</topic><topic>DNA Methyltransferase 3B</topic><topic>Enhancer Elements, Genetic - genetics</topic><topic>Entropy</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Human Embryonic Stem Cells - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Repressor Proteins - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Stem Cells and Regeneration</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tsankov, Alexander M</creatorcontrib><creatorcontrib>Wadsworth, 2nd, Marc H</creatorcontrib><creatorcontrib>Akopian, Veronika</creatorcontrib><creatorcontrib>Charlton, Jocelyn</creatorcontrib><creatorcontrib>Allon, Samuel J</creatorcontrib><creatorcontrib>Arczewska, Aleksandra</creatorcontrib><creatorcontrib>Mead, Benjamin E</creatorcontrib><creatorcontrib>Drake, Riley S</creatorcontrib><creatorcontrib>Smith, Zachary D</creatorcontrib><creatorcontrib>Mikkelsen, Tarjei S</creatorcontrib><creatorcontrib>Shalek, Alex K</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Development (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsankov, Alexander M</au><au>Wadsworth, 2nd, Marc H</au><au>Akopian, Veronika</au><au>Charlton, Jocelyn</au><au>Allon, Samuel J</au><au>Arczewska, Aleksandra</au><au>Mead, Benjamin E</au><au>Drake, Riley S</au><au>Smith, Zachary D</au><au>Mikkelsen, Tarjei S</au><au>Shalek, Alex K</au><au>Meissner, Alexander</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2019-09-12</date><risdate>2019</risdate><volume>146</volume><issue>19</issue><issn>0950-1991</issn><eissn>1477-9129</eissn><abstract>Maintenance of pluripotency and specification towards a new cell fate are both dependent on precise interactions between extrinsic signals and transcriptional and epigenetic regulators. Directed methylation of cytosines by the
methyltransferases DNMT3A and DNMT3B plays an important role in facilitating proper differentiation, whereas DNMT1 is essential for maintaining global methylation levels in all cell types. Here, we generated single-cell mRNA expression data from wild-type, DNMT3A, DNMT3A/3B and DNMT1 knockout human embryonic stem cells and observed a widespread increase in cellular and transcriptional variability, even with limited changes in global methylation levels in the
knockouts. Furthermore, we found unexpected transcriptional repression upon either loss of the
methyltransferase DNMT3A or the double knockout of DNMT3A/3B that is further propagated upon differentiation to mesoderm and ectoderm. Taken together, our single-cell RNA-sequencing data provide a high-resolution view into the consequences of depleting the three catalytically active DNMTs in human pluripotent stem cells.</abstract><cop>England</cop><pub>The Company of Biologists Ltd</pub><pmid>31515224</pmid><doi>10.1242/dev.174722</doi><orcidid>https://orcid.org/0000-0002-7955-4414</orcidid><orcidid>https://orcid.org/0000-0001-8646-7469</orcidid><orcidid>https://orcid.org/0000-0001-5670-8778</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Development (Cambridge), 2019-09, Vol.146 (19) |
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| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Company of Biologists |
| subjects | Cell Cycle - genetics Cell Differentiation - genetics DNA (Cytosine-5-)-Methyltransferase 1 - metabolism DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation - genetics DNA Methyltransferase 3A DNA Methyltransferase 3B Enhancer Elements, Genetic - genetics Entropy Gene Expression Regulation, Developmental Human Embryonic Stem Cells - metabolism Humans Male Repressor Proteins - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Stem Cells and Regeneration Transcription, Genetic |
| title | Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression |
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