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 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.
Young
Juan I
JI
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Hong
Eugene P
EP
Castle
John C
JC
Crespo-Barreto
Juan
J
Bowman
Aaron B
AB
Rose
Matthew F
MF
Kang
Dongcheul
D
Richman
Ron
R
Johnson
Jason M
JM
Berget
Susan
S
Zoghbi
Huda Y
HY
D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D011485:Protein Binding; D012313:RNA / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
D051783:Methyl-CpG-Binding Protein 2; D012313:RNA