Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping.
Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping.
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DOI：
10.1016/j.molcel.2009.12.003
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发表时间：
2009-12-25
期刊：
影响因子：
16
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Xue Y;Zhou Y;Wu T;Zhu T;Ji X;Kwon YS;Zhang C;Yeo G;Black DL;Sun H;Fu XD;Zhang Y
最近的转录组分析表明，> 90%的人类基因经历选择性剪接，强调了差异RNA加工对高等真核细胞中不同蛋白质组的贡献。多聚嘧啶段结合蛋白PTB是一种特征良好的剪接阻遏物，但PTB敲低导致外显子包含和跳跃。PTB-RNA相互作用的全基因组作图和功能性RNA图谱的构建现在揭示，在竞争性组成性剪接位点附近的显性PTB结合通常诱导外显子包含，而在替代位点附近的普遍结合通常导致外显子跳跃。通过破坏或在小基因构建体上产生PTB结合位点并测试它们对PTB敲低或过表达的响应，进一步证明了这种位置效应。这些发现表明PTB调节剪接位点竞争以产生相反的功能结果的机制，这可能通常适用于RNA结合剪接因子以正向或负向调节哺乳动物细胞中的选择性剪接。
Recent transcriptome analysis indicates that >90% of human genes undergoes alternative splicing, underscoring the contribution of differential RNA processing to diverse proteomes in higher eukaryotic cells. The polypyrimidine tract binding protein PTB is a well-characterized splicing repressor, but PTB knockdown causes both exon inclusion and skipping. Genome-wide mapping of PTB-RNA interactions and construction of a functional RNA map now revealed that dominant PTB binding near a competing constitutive splice site generally induces exon inclusion whereas prevalent binding close to an alternative site often causes exon skipping. This positional effect was further demonstrated by disrupting or creating a PTB binding site on minigene constructs and testing their responses to PTB knockdown or overexpression. These findings suggest a mechanism for PTB to modulate splice site competition to produce opposite functional consequences, which may be generally applicable to RNA binding splicing factors to positively or negatively regulate alternative splicing in mammalian cells.
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