HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.
HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.
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DOI：
10.1016/j.celrep.2014.02.005
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发表时间：
2014-03-27
期刊：
影响因子：
8.8
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Weyn-Vanhentenryck SM;Mele A;Yan Q;Sun S;Farny N;Zhang Z;Xue C;Herre M;Silver PA;Zhang MQ;Krainer AR;Darnell RB;Zhang C
RNA结合蛋白Rbfox 1/2/3调节神经系统中的选择性剪接，Rbfox 1的破坏与自闭症有关。然而，全面鉴定功能性Rbfox靶标一直具有挑战性。在这里，我们对所有三个Rbfox家族成员进行了HITS-CLIP，以单核苷酸分辨率全局映射它们在小鼠大脑中的体内RNA相互作用位点。我们发现Rbfox结合基序UGCAUG中的两个鸟嘌呤对蛋白质-RNA相互作用和交联至关重要。使用整合建模，这些相互作用位点与额外的数据集相结合，定义了1，059个直接Rbfox靶向选择性剪接事件。超过一半的可量化目标显示出大脑发育过程中的动态变化。特别令人感兴趣的是来自48个候选自闭症易感基因的111个事件，包括综合征型自闭症基因Shank 3，Cacna 1c和Tsc 2。在一些自闭症大脑中Rbfox靶点的改变与所有三种Rbfox蛋白的下调相关，支持剪接-调节网络的潜在临床相关性。
The RNA-binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system, and disruption of Rbfox1 has been implicated in autism. However, comprehensive identification of functional Rbfox targets has been challenging. Here we performed HITS-CLIP for all three Rbfox family members to globally map, at a single-nucleotide resolution, their in vivo RNA interaction sites in the mouse brain. We found that the two guanines in the Rbfox-binding motif UGCAUG are critical for protein-RNA interactions and crosslinking. Using integrative modeling, these interaction sites combined with additional datasets defined 1,059 direct Rbfox target alternative splicing events. Over half of the quantifiable targets show dynamic changes during brain development. Of particular interest are 111 events from 48 candidate autism-susceptibility genes, including syndromic autism genes Shank3, Cacna1c, and Tsc2. Alteration of Rbfox targets in some autistic brains is correlated with down-regulation of all three Rbfox proteins, supporting the potential clinical relevance of the splicing- regulatory network.
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