Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor

In this study, the authors show that MeCP2 interacts with the NCoR/SMRT co-repressor complex and that a discrete cluster of Rett syndrome–causing mutations in the C-terminal domain of MeCP2 disrupts this interaction, impairing transcriptional repression. Knock-in mice expressing one of these MeCP2 m...

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Veröffentlicht in:Nature neuroscience 2013-07, Vol.16 (7), p.898-902
Hauptverfasser: Lyst, Matthew J, Ekiert, Robert, Ebert, Daniel H, Merusi, Cara, Nowak, Jakub, Selfridge, Jim, Guy, Jacky, Kastan, Nathaniel R, Robinson, Nathaniel D, de Lima Alves, Flavia, Rappsilber, Juri, Greenberg, Michael E, Bird, Adrian
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container_end_page 902
container_issue 7
container_start_page 898
container_title Nature neuroscience
container_volume 16
creator Lyst, Matthew J
Ekiert, Robert
Ebert, Daniel H
Merusi, Cara
Nowak, Jakub
Selfridge, Jim
Guy, Jacky
Kastan, Nathaniel R
Robinson, Nathaniel D
de Lima Alves, Flavia
Rappsilber, Juri
Greenberg, Michael E
Bird, Adrian
description In this study, the authors show that MeCP2 interacts with the NCoR/SMRT co-repressor complex and that a discrete cluster of Rett syndrome–causing mutations in the C-terminal domain of MeCP2 disrupts this interaction, impairing transcriptional repression. Knock-in mice expressing one of these MeCP2 missense mutations exhibit severe motor phenotypes. Rett syndrome (RTT) is a severe neurological disorder that is caused by mutations in the MECP2 gene. Many missense mutations causing RTT are clustered in the DNA-binding domain of MeCP2, suggesting that association with chromatin is critical for its function. We identified a second mutational cluster in a previously uncharacterized region of MeCP2. We found that RTT mutations in this region abolished the interaction between MeCP2 and the NCoR/SMRT co-repressor complexes. Mice bearing a common missense RTT mutation in this domain exhibited severe RTT-like phenotypes. Our data are compatible with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 'bridge' between the NCoR/SMRT co-repressors and chromatin.
doi_str_mv 10.1038/nn.3434
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subjects 631/208/200
631/378/1689/1373
631/378/340
Amino acids
Animal Genetics and Genomics
Animals
Antibodies
Behavioral Sciences
Binding proteins
Biological Techniques
Biomedicine
Brain
Brain - metabolism
Brain - pathology
Cells, Cultured
Chromatin
Disease Models, Animal
DNA methylation
Exploratory Behavior - physiology
Genetic aspects
Green Fluorescent Proteins - genetics
Histone Deacetylases - genetics
Histone Deacetylases - metabolism
Immunoprecipitation
Methyl-CpG-Binding Protein 2 - genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Molecular
Mutation
Mutation - genetics
Neurobiology
Neurosciences
Nuclear Receptor Co-Repressor 1 - genetics
Nuclear Receptor Co-Repressor 1 - metabolism
Nuclear Receptor Co-Repressor 2 - genetics
Nuclear Receptor Co-Repressor 2 - metabolism
Peptides
Properties
Proteins
Repressor proteins
Rett syndrome
Rett Syndrome - genetics
Rett Syndrome - pathology
Rett Syndrome - physiopathology
title Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor
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