Regulation of RNA Splicing by the Methylation-Dependent Transcriptional Repressor Methyl-CpG Binding Protein 2

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 caus...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-12, Vol.102 (49), p.17551-17558
Main Authors: Juan I. Young, Eugene P. Hong, John C. Castle, Juan Crespo-Barreto, Bowman, Aaron B., Matthew F. Rose, Dongcheul Kang, Richman, Ron, Johnson, Jason M., Susan Berget, Zoghbi, Huda Y.
Format: Article
Language:English
Subjects:
Alternative splicing
Animals
Antibodies
Biological Sciences
Cell Line, Tumor
DNA
DNA Methylation
Exons
Exons - genetics
Gene Expression Profiling
Genes, Reporter - genetics
HeLa cells
Humans
Messenger RNA
Methyl-CpG-Binding Protein 2 - genetics
Methyl-CpG-Binding Protein 2 - metabolism
Mice
Models, Genetic
Neurons
Protein Binding
Proteins
Rett Syndrome - genetics
RNA
RNA - genetics
RNA Splicing - genetics
Splicing
Transcription, Genetic - genetics
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Summary:Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0507856102