A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome
A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome
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DOI：
10.1007/s12035-018-1412-2
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Landsberger, Nicoletta
中科院分区：
文献类型：
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作者：
Gandaglia, Anna;Brivio, Elena;Landsberger, Nicoletta
MeCP2是一种与包括Rett综合征在内的几种神经系统疾病相关的基本蛋白。它被认为是一种多功能因子，在调节染色质结构中起着重要作用；然而，仍然缺乏对其不足的后果的充分理解。在这里，我们描述了一种携带人类突变Y120D的Mecp2小鼠模型，该突变定位于甲基结合域。与大多数Mecp2模型一样，Mecp2Y120D小鼠表现出严重的ret样表型。这种突变改变了蛋白质与染色质的相互作用，但令人惊讶的是，它也在相关的相互作用域上独立地损害了它与辅抑制子的联系。这些特征主要在成熟的大脑中变得明显，导致更容易接近和转录活跃的染色质结构；相反，在mecp2缺失的大脑中，我们发现了一种不易接近且转录不活跃的染色质。通过证明不同的MECP2突变可以产生一致的神经表型，但不一致的分子特征，我们强调了考虑个性化方法治疗Rett综合征的重要性。
MeCP2 is a fundamental protein associated with several neurological disorders, including Rett syndrome. It is considered a multifunctional factor with a prominent role in regulating chromatin structure; however, a full comprehension of the consequences of its deficiency is still lacking. Here, we characterize a novel mouse model of Mecp2 bearing the human mutation Y120D, which is localized in the methyl-binding domain. As most models of Mecp2, the Mecp2Y120D mouse develops a severe Rett-like phenotype. This mutation alters the interaction of the protein with chromatin, but surprisingly, it also impairs its association with corepressors independently on the involved interacting domains. These features, which become overt mainly in the mature brain, cause a more accessible and transcriptionally active chromatin structure; conversely, in the Mecp2-null brain, we find a less accessible and transcriptionally inactive chromatin. By demonstrating that different MECP2 mutations can produce concordant neurological phenotypes but discordant molecular features, we highlight the importance of considering personalized approaches for the treatment of Rett syndrome.