Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 17551-17558 |
| Number of pages | 8 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 49 |
| DOIs | |
| State | Published - Dec 6 2005 |
| Externally published | Yes |
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Keywords
- Rett syndrome
- Y box-binding protein 1
ASJC Scopus subject areas
- Genetics
- General
Cite this
Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. / Young, Juan; Hong, Eugene P.; Castle, John C.; Crespo-Barreto, Juan; Bowman, Aaron B.; Rose, Matthew F.; Kang, Dongcheul; Richman, Ron; Johnson, Jason M.; Berget, Susan; Zoghbi, Huda Y.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 49, 06.12.2005, p. 17551-17558.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2
AU - Young, Juan
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.
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
UR - http://www.scopus.com/inward/record.url?scp=29144447632&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29144447632&partnerID=8YFLogxK
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 -