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...

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Bibliographic Details
Published in:Nature (London) 2013-06, Vol.498 (7453), p.241-245
Main Authors: Han, Hong, Irimia, Manuel, Ross, P Joel, Sung, Hoon-Ki, Alipanahi, Babak, David, Laurent, Golipour, Azadeh, Gabut, Mathieu, Michael, Iacovos P, Nachman, Emil N, Wang, Eric, Trcka, Dan, Thompson, Tadeo, O'Hanlon, Dave, Slobodeniuc, Valentina, Barbosa-Morais, Nuno L, Burge, Christopher B, Moffat, Jason, Frey, Brendan J, Nagy, Andras, Ellis, James, Wrana, Jeffrey L, Blencowe, Benjamin J
Format: Article
Language:English
Subjects:
Alternative Splicing - genetics
Amino Acid Motifs
Animals
Binding proteins
Binding sites
Biology
Cell Differentiation - genetics
Cell Line
Cellular Reprogramming
Cloning
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Embryonic stem cells
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Fibroblasts - cytology
Fibroblasts - metabolism
Forkhead Transcription Factors - metabolism
Gene expression
Gene Knockdown Techniques
Genetic aspects
Genetic engineering
Genetic regulation
HEK293 Cells
HeLa Cells
Humans
Identification and classification
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Kinases
Kinetics
Mice
Physiological aspects
Proteins
Repressor Proteins - metabolism
RNA splicing
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Testing
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Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature12270