Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2.

Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY
Proc Natl Acad Sci U S A. 2005 102 (49): 17551-8

PMID: 16251272 · PMCID: PMC1266160 · DOI:10.1073/pnas.0507856102

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.

MeSH Terms (15)

Animals Cell Line, Tumor DNA Methylation Exons Gene Expression Profiling Genes, Reporter Humans Methyl-CpG-Binding Protein 2 Mice Models, Genetic Protein Binding Rett Syndrome RNA RNA Splicing Transcription, Genetic

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