Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1γ gene
Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1γ gene
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DOI：
10.1093/nar/gkm569
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发表时间：
2007-08-01
影响因子：
14.9
通讯作者：
Inoue, Kunio
中科院分区：
文献类型：
--
作者：
Fukumura, Kazuhiro;Kato, Ayako;Inoue, Kunio
Fox-1是组织特异性剪接的调节因子，通过与肌肉和神经元细胞中mRNA前体中的元件（U）GCAUG结合。Fox-1可以正向或负向调节剪接，最有可能取决于它相对于受调节外显子的结合位置。在（U）GCAUG元件位于选择性外显子上游的内含子中的情况下，Fox-1蛋白充当剪接阻遏物以诱导外显子跳跃。在这里，我们报告的机制外显子跳跃福克斯1调节，使用hF 1 γ基因作为模型系统。我们发现Fox-1通过与位于上游内含子8中的GCAUG阻遏物元件结合来抑制下游内含子9的剪接，从而诱导外显子9跳跃。体外剪接分析表明，Fox-1阻止内含子9上的前剪接体早期（E）复合物的形成。此外，我们还定位了Fox-1蛋白的一个区域，该区域是诱导外显子跳跃所必需的。总之，我们的数据显示了RNA结合蛋白如何调节选择性剪接的新机制。
Fox-1 is a regulator of tissue-specific splicing, via binding to the element (U) GCAUG in mRNA precursors, in muscles and neuronal cells. Fox-1 can regulate splicing positively or negatively, most likely depending on where it binds relative to the regulated exon. In cases where the (U) GCAUG element lies in an intron upstream of the alternative exon, Fox-1 protein functions as a splicing repressor to induce exon skipping. Here we report the mechanism of exon skipping regulated by Fox-1, using the hF1 gamma gene as a model system. We found that Fox-1 induces exon 9 skipping by repressing splicing of the downstream intron 9 via binding to the GCAUG repressor elements located in the upstream intron 8. In vitro splicing analyses showed that Fox-1 prevents formation of the pre-spliceosomal early (E) complex on intron 9. In addition, we located a region of the Fox-1 protein that is required for inducing exon skipping. Taken together, our data show a novel mechanism of how RNA-binding proteins regulate alternative splicing.