DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome
DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome
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DOI：
10.1093/hmg/ddp047
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发表时间：
2009-04-15
影响因子：
3.5
通讯作者：
Simonneau, Michel
中科院分区：
文献类型：
--
作者：
Lepagnol-Bestel, Aude-Marie;Zvara, Agnes;Simonneau, Michel
唐氏综合征（DS）是导致智力迟钝的最常见原因，导致其认知缺陷的分子机制仍然难以捉摸。在这里，我们使用一个转基因DS小鼠模型（152 F7线），表明DYRK 1A基因剂量失衡失调染色体簇的基因位于神经元限制性沉默因子（REST/NRSF）结合位点附近。我们发现Dyrk 1a结合SWI/SNF复合物，已知与REST/NRSF相互作用。REST/NRSF靶基因L1 cam启动子中REST/NRSF结合位点的突变改变了Dyrk 1a剂量失衡对L1 cam的转录效应。Dyrk 1a剂量失衡干扰Rest/Nrsf水平，胚胎神经元中Rest/Nrsf表达降低，成年神经元中表达增加。使用转基因152 F7小鼠系的胚胎脑亚区的转录组分析，我们确定了一个协调失调的多个基因，负责树突状细胞生长障碍目前在DS。类似地，Dyrk 1a在原代小鼠皮层神经元中的过表达诱导树突生长和树突复杂性的严重减少。我们提出，DYRK 1A过表达相关的神经元基因失调通过干扰REST/NRSF水平，和REST/NRSF-SWI/SNF染色质重塑复合物，显着有助于神经表型的变化，表征DS。
The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.