Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons
Rett syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbi...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/102529 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-9168-0109 https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-8855-8647 https://orcid.org/0000-0002-6883-3805 |
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| author | Li, Yun Wang, Haoyi Muffat, Julien Cheng, Albert W. Orlando, David A. Feldman, Danielle A. Bateup, Helen S. Gao, Qing Hockemeyer, Dirk Mitalipova, Maisam Lewis, Caroline A. Sur, Mriganka Young, Richard A. Jaenisch, Rudolf Loven, Jakob Vander Heiden, Matthew G. Feldman, Danielle A. Young, Richard A. Lewis, Caroline Kwok, Show Ming |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Li, Yun Wang, Haoyi Muffat, Julien Cheng, Albert W. Orlando, David A. Feldman, Danielle A. Bateup, Helen S. Gao, Qing Hockemeyer, Dirk Mitalipova, Maisam Lewis, Caroline A. Sur, Mriganka Young, Richard A. Jaenisch, Rudolf Loven, Jakob Vander Heiden, Matthew G. Feldman, Danielle A. Young, Richard A. Lewis, Caroline Kwok, Show Ming |
| author_sort | Li, Yun |
| collection | MIT |
| description | Rett syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbiased global gene expression analyses demonstrate that MECP2 functions as a global activator in neurons but not in neural precursors. Decreased transcription in neurons was coupled with a significant reduction in nascent protein synthesis and lack of MECP2 was manifested as a severe defect in the activity of the AKT/mTOR pathway. Lack of MECP2 also leads to impaired mitochondrial function in mutant neurons. Activation of AKT/mTOR signaling by exogenous growth factors or by depletion of PTEN boosted protein synthesis and ameliorated disease phenotypes in mutant neurons. Our findings indicate a vital function for MECP2 in maintaining active gene transcription in human neuronal cells. |
| first_indexed | 2024-09-23T14:30:23Z |
| format | Article |
| id | mit-1721.1/102529 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:30:23Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1025292022-10-01T21:34:37Z Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons Li, Yun Wang, Haoyi Muffat, Julien Cheng, Albert W. Orlando, David A. Feldman, Danielle A. Bateup, Helen S. Gao, Qing Hockemeyer, Dirk Mitalipova, Maisam Lewis, Caroline A. Sur, Mriganka Young, Richard A. Jaenisch, Rudolf Loven, Jakob Vander Heiden, Matthew G. Feldman, Danielle A. Young, Richard A. Lewis, Caroline Kwok, Show Ming Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Kwok, Show-ming Feldman, Danielle A. Lewis, Caroline A. Vander Heiden, Matthew G. Sur, Mriganka Young, Richard A. Jaenisch, Rudolf Rett syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbiased global gene expression analyses demonstrate that MECP2 functions as a global activator in neurons but not in neural precursors. Decreased transcription in neurons was coupled with a significant reduction in nascent protein synthesis and lack of MECP2 was manifested as a severe defect in the activity of the AKT/mTOR pathway. Lack of MECP2 also leads to impaired mitochondrial function in mutant neurons. Activation of AKT/mTOR signaling by exogenous growth factors or by depletion of PTEN boosted protein synthesis and ameliorated disease phenotypes in mutant neurons. Our findings indicate a vital function for MECP2 in maintaining active gene transcription in human neuronal cells. National Institutes of Health (U.S.) (Grant R01-HG002668) National Cancer Institute (U.S.) (P30-CA14051) David H. Koch Institute for Integrative Cancer Research at MIT Kathy and Curt Marble Cancer Research Fund National Institutes of Health (U.S.) (Grant HD 045022) National Institutes of Health (U.S.) (Grant R37-CA084198) Simons Foundation European Leukodystrophy Association 2016-05-18T17:10:26Z 2016-05-18T17:10:26Z 2013-10 Article http://purl.org/eprint/type/JournalArticle 19345909 http://hdl.handle.net/1721.1/102529 Li, Yun, Haoyi Wang, Julien Muffat, Albert W. Cheng, David A. Orlando, Jakob Loven, Show-ming Kwok, et al. “Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons.” Cell Stem Cell 13, no. 4 (October 2013): 446–58. https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-9168-0109 https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-8855-8647 https://orcid.org/0000-0002-6883-3805 en_US http://dx.doi.org/10.1016/j.stem.2013.09.001 Cell Stem Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Li, Yun Wang, Haoyi Muffat, Julien Cheng, Albert W. Orlando, David A. Feldman, Danielle A. Bateup, Helen S. Gao, Qing Hockemeyer, Dirk Mitalipova, Maisam Lewis, Caroline A. Sur, Mriganka Young, Richard A. Jaenisch, Rudolf Loven, Jakob Vander Heiden, Matthew G. Feldman, Danielle A. Young, Richard A. Lewis, Caroline Kwok, Show Ming Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title | Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title_full | Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title_fullStr | Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title_full_unstemmed | Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title_short | Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons |
| title_sort | global transcriptional and translational repression in human embryonic stem cell derived rett syndrome neurons |
| url | http://hdl.handle.net/1721.1/102529 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0001-9168-0109 https://orcid.org/0000-0003-2442-5671 https://orcid.org/0000-0001-8855-8647 https://orcid.org/0000-0002-6883-3805 |
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