MBNL proteins repress ES-cell-specific alternative splicing and reprogramming
Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/1721.1/96291 |
| _version_ | 1811072192388005888 |
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| author | Han, Hong Irimia, Manuel Ross, P. Joel Sung, Hoon-Ki Alipanahi, Babak David, Laurent Golipour, Azadeh Gabut, Mathieu Michael, Iacovos P. Nachman, Emil N. Trcka, Dan Thompson, Tadeo O’Hanlon, Dave Slobodeniuc, Valentina Barbosa-Morais, Nuno L. Moffat, Jason Frey, Brendan J. Nagy, Andras Ellis, James Wrana, Jeffrey L. Blencowe, Benjamin J. Wang, Eric T Burge, Christopher B |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Han, Hong Irimia, Manuel Ross, P. Joel Sung, Hoon-Ki Alipanahi, Babak David, Laurent Golipour, Azadeh Gabut, Mathieu Michael, Iacovos P. Nachman, Emil N. Trcka, Dan Thompson, Tadeo O’Hanlon, Dave Slobodeniuc, Valentina Barbosa-Morais, Nuno L. Moffat, Jason Frey, Brendan J. Nagy, Andras Ellis, James Wrana, Jeffrey L. Blencowe, Benjamin J. Wang, Eric T Burge, Christopher B |
| author_sort | Han, Hong |
| collection | MIT |
| description | Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES-cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ES-cell-like alternative splicing pattern for approximately half of these events, whereas overexpression of MBNL proteins in ES cells promotes differentiated-cell-like alternative splicing patterns. Among the MBNL-regulated events is an ES-cell-specific alternative splicing switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming. |
| first_indexed | 2024-09-23T09:02:04Z |
| format | Article |
| id | mit-1721.1/96291 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:02:04Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/962912022-09-30T12:56:55Z MBNL proteins repress ES-cell-specific alternative splicing and reprogramming Han, Hong Irimia, Manuel Ross, P. Joel Sung, Hoon-Ki Alipanahi, Babak David, Laurent Golipour, Azadeh Gabut, Mathieu Michael, Iacovos P. Nachman, Emil N. Trcka, Dan Thompson, Tadeo O’Hanlon, Dave Slobodeniuc, Valentina Barbosa-Morais, Nuno L. Moffat, Jason Frey, Brendan J. Nagy, Andras Ellis, James Wrana, Jeffrey L. Blencowe, Benjamin J. Wang, Eric T Burge, Christopher B Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Wang, Eric Tzy-shi Burge, Christopher B. Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES-cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ES-cell-like alternative splicing pattern for approximately half of these events, whereas overexpression of MBNL proteins in ES cells promotes differentiated-cell-like alternative splicing patterns. Among the MBNL-regulated events is an ES-cell-specific alternative splicing switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming. Canadian Institutes of Health Research (grant) Ontario Research Foundation Stem Cell Network (Canada) National Institutes of Health (U.S.) (grant R33MH087908) University of Toronto (Open Fellowship) Ontario Stem Cell Initiative Human Frontier Science Program (Strasbourg, France) European Union (Marie Curie Actions) 2015-03-31T19:17:28Z 2015-03-31T19:17:28Z 2013-06 2012-09 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/96291 Han, Hong, Manuel Irimia, P. Joel Ross, Hoon-Ki Sung, Babak Alipanahi, Laurent David, Azadeh Golipour, et al. “MBNL Proteins Repress ES-Cell-Specific Alternative Splicing and Reprogramming.” Nature 498, no. 7453 (June 5, 2013): 241–245. en_US http://dx.doi.org/10.1038/nature12270 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Han, Hong Irimia, Manuel Ross, P. Joel Sung, Hoon-Ki Alipanahi, Babak David, Laurent Golipour, Azadeh Gabut, Mathieu Michael, Iacovos P. Nachman, Emil N. Trcka, Dan Thompson, Tadeo O’Hanlon, Dave Slobodeniuc, Valentina Barbosa-Morais, Nuno L. Moffat, Jason Frey, Brendan J. Nagy, Andras Ellis, James Wrana, Jeffrey L. Blencowe, Benjamin J. Wang, Eric T Burge, Christopher B MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title | MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title_full | MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title_fullStr | MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title_full_unstemmed | MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title_short | MBNL proteins repress ES-cell-specific alternative splicing and reprogramming |
| title_sort | mbnl proteins repress es cell specific alternative splicing and reprogramming |
| url | http://hdl.handle.net/1721.1/96291 |
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