Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping.
Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping.
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DOI：
10.1261/rna.065383.117
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Potter PM
中科院分区：
文献类型：
--
作者：
Wu G;Fan L;Edmonson MN;Shaw T;Boggs K;Easton J;Rusch MC;Webb TR;Zhang J;Potter PM
最近发现的与剪接体相互作用的化合物(Sudemycins、Spliceostatin A和Meayamcin)表明，这些分子通过抑制SF3B1来调节异常剪接。通过整个转录组测序，我们已经证明了苏德霉素处理Rh18细胞会导致外显子跳跃作为主要的异常剪接事件。这也是在对来自HeLa细胞的已发表的RNA-seq数据集进行重新分析后观察到的，这些数据来自于Spliceostatin A暴露。这些结果与以前的报告相反，以前的报告表明内含子保留是SF3B1抑制的主要结果。对这些小分子上调的外显子连接的分析表明，这些序列在注释的人类基因中不存在，这表明异常剪接事件产生了新的RNA转录本。有趣的是，首选的下游外显子的长度明显长于跳过的外显子，尽管跳过的外显子两侧的内含子的长度没有差异。异常跳跃的外显子的阅读框架维持在2：1：1的比率，接近以自然产生的亚型存在的盒式外显子的阅读框架(3：1：1)，这表明无意义介导的衰退(NMD)机制对框架外转录的负选择。因此，参与NMD的基因和编码参与剪接过程的蛋白质的RNA在两个数据集中都得到了丰富。因此，我们的发现进一步阐明了SF3B1抑制调控前mRNA剪接的机制。
The recent identification of compounds that interact with the spliceosome (sudemycins, spliceostatin A, and meayamycin) indicates that these molecules modulate aberrant splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNA-seq data sets derived from HeLa cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition. Analysis of the exon junctions up-regulated by these small molecules indicated that these sequences were absent in annotated human genes, suggesting that aberrant splicing events yielded novel RNA transcripts. Interestingly, the length of preferred downstream exons was significantly longer than the skipped exons, although there was no difference between the lengths of introns flanking skipped exons. The reading frame of the aberrantly skipped exons maintained a ratio of 2:1:1, close to that of the cassette exons (3:1:1) present in naturally occurring isoforms, suggesting negative selection by the nonsense-mediated decay (NMD) machinery for out-of-frame transcripts. Accordingly, genes involved in NMD and RNAs encoding proteins involved in the splicing process were enriched in both data sets. Our findings, therefore, further elucidate the mechanisms by which SF3B1 inhibition modulates pre-mRNA splicing.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
12.3
作者：
Robinson MD;Oshlack A
通讯作者：
Oshlack A
影响因子：
12.3
作者：
Sterne-Weiler T;Sanford JR
通讯作者：
Sanford JR
影响因子：
16.6
作者：
Teng T;Tsai JH;Puyang X;Seiler M;Peng S;Prajapati S;Aird D;Buonamici S;Caleb B;Chan B;Corson L;Feala J;Fekkes P;Gerard B;Karr C;Korpal M;Liu X;T Lowe J;Mizui Y;Palacino J;Park E;Smith PG;Subramanian V;Wu ZJ;Zou J;Yu L;Chicas A;Warmuth M;Larsen N;Zhu P
通讯作者：
Zhu P