Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2
Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2
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DOI：
10.1073/pnas.0507856102
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发表时间：
2005-12-06
影响因子：
11.1
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Young, JI;Hong, EP;Zoghbi, HY
Rett综合征（RTT）是一种产后神经发育障碍，其特征是丧失获得性运动和语言技能、自闭症特征和不寻常的刻板动作。RTT是由编码甲基cpg结合蛋白2 （MeCP2）的x连锁基因突变引起的。MECP2的突变导致多种神经发育障碍，包括x连锁智力迟钝、精神障碍和一些自闭症病例。尽管MeCP2被鉴定为甲基化依赖性转录抑制因子，但缺乏MeCP2小鼠的rna转录谱分析并未显示出显著的基因表达变化，这表明MeCP2不仅仅是一种全局抑制因子。已经观察到一些基因的表达变化，但这些变化并不能解释rett样表型的全部谱系，这就提出了MeCP2功能在发病机制中发挥作用的可能性。在这项研究中，我们发现MeCP2与rna结合蛋白Y盒结合蛋白1相互作用，并调节报告基因的剪接。重要的是，我们在RTT小鼠模型中发现了异常的选择性剪接模式。因此，我们发现了MeCP2除了作为转录抑制因子的作用外，还涉及剪接调节的先前未被描述的功能。
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.