TY - JOUR
T1 - Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2
AU - Young, Juan I.
AU - Hong, Eugene P.
AU - Castle, John C.
AU - Crespo-Barreto, Juan
AU - Bowman, Aaron B.
AU - Rose, Matthew F.
AU - Kang, Dongcheul
AU - Richman, Ron
AU - Johnson, Jason M.
AU - Berget, Susan
AU - Zoghbi, Huda Y.
N1 - Funding Information:
Embark scheme and Science Foundation Ireland (SFI) under the UREKA scheme. Carlos Elvira acknowledges MEC for the financial support during his sabbatical stay at the NCBES, National University of Ireland, Galway, Ireland.
Funding Information:
We gratefully acknowledge the financial support received from The Irish Research Council under the
PY - 2005/12/6
Y1 - 2005/12/6
N2 - 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.
AB - 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.
KW - Rett syndrome
KW - Y box-binding protein 1
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U2 - 10.1073/pnas.0507856102
DO - 10.1073/pnas.0507856102
M3 - Article
C2 - 16251272
AN - SCOPUS:29144447632
VL - 102
SP - 17551
EP - 17558
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 49
ER -