Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.
Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.
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DOI：
10.1038/nn.3434
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发表时间：
2013-07
影响因子：
25
通讯作者：
Bird, Adrian
中科院分区：
文献类型：
--
作者：
Lyst, Matthew J.;Ekiert, Robert;Ebert, Daniel H.;Merusi, Cara;Nowak, Jakub;Selfridge, Jim;Guy, Jacky;Kastan, Nathaniel R.;Robinson, Nathaniel D.;Alves, Flavia de Lima;Rappsilber, Juri;Greenberg, Michael E.;Bird, Adrian
Rett综合征（RTT）是一种由MECP2基因突变引起的严重神经系统疾病。许多引起RTT的错义突变聚集在MeCP2的dna结合区域，这表明与染色质的关联对其功能至关重要。我们在MeCP2先前未表征的区域发现了第二个突变簇。我们发现该区域的RTT突变消除了MeCP2与NCoR/SMRT共抑制复合物之间的相互作用。在该区域携带常见错义RTT突变的小鼠表现出严重的RTT样表型。我们的数据与RTT脑功能障碍是由NCoR/SMRT共抑制因子和染色质之间的MeCP2“桥”缺失引起的假设相一致。
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.
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