Mathematical modeling identifies potential gene structure determinants of co-transcriptional control of alternative pre-mRNA splicing.
Mathematical modeling identifies potential gene structure determinants of co-transcriptional control of alternative pre-mRNA splicing.
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DOI：
10.1093/nar/gky870
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发表时间：
2018-11-16
影响因子：
14.9
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Davis-Turak J;Johnson TL;Hoffmann A
剪接体催化从前信使RNA （mRNA）中去除内含子和随后的外显子配对，具有显著的保真度。已知一些外显子以细胞类型或上下文依赖的方式被跳过或包含在成熟mRNA中（盒式外显子），从而有助于人类蛋白质组的多样化。有趣的是，剪接是通过共转录启动（有时完成）的。在这里，我们开发了一个动力学数学模型框架来研究选择性共转录剪接（CTS），特别是盒式外显子包含的控制。我们表明，当剪接是共转录时，外显子包含的默认剪接模式比剪接是转录后的剪接更有可能，并且基于外显子-内含子结构背景，某些外显子（即盒式外显子）比其他外显子更有可能是可调节的。对于这些可调节的外显子，转录延伸率可能影响剪接结果。在CTS范式中，我们检查了先前描述的短内含子剪接位点之间（即“内含子定义”）或跨短外显子剪接位点（即“外显子定义”）的合作假设，并发现编码这些模型忠实地分别概括了苍蝇和人类基因组中的观察结果。
The spliceosome catalyzes the removal of introns from pre-messenger RNA (mRNA) and subsequent pairing of exons with remarkable fidelity. Some exons are known to be skipped or included in the mature mRNA in a cell type- or context-dependent manner (cassette exons), thereby contributing to the diversification of the human proteome. Interestingly, splicing is initiated (and sometimes completed) co-transcriptionally. Here, we develop a kinetic mathematical modeling framework to investigate alternative co-transcriptional splicing (CTS) and, specifically, the control of cassette exons’ inclusion. We show that when splicing is co-transcriptional, default splice patterns of exon inclusion are more likely than when splicing is post-transcriptional, and that certain exons are more likely to be regulatable (i.e. cassette exons) than others, based on the exon–intron structure context. For such regulatable exons, transcriptional elongation rates may affect splicing outcomes. Within the CTS paradigm, we examine previously described hypotheses of co-operativity between splice sites of short introns (i.e. ‘intron definition’) or across short exons (i.e. ‘exon definition’), and find that models encoding these faithfully recapitulate observations in the fly and human genomes, respectively.
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DOI：
10.1083/jcb.201004030
发表时间：
2010-10-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Huranová M;Ivani I;Benda A;Poser I;Brody Y;Hof M;Shav-Tal Y;Neugebauer KM;Stanek D
通讯作者：
Stanek D
影响因子：
5.3
作者：
MING, G;LO, PCH;MOUNT, SM
通讯作者：
MOUNT, SM
影响因子：
4.5
作者：
de la Mata, Manuel;Lafaille, Celina;Kornblihtt, Alberto R.
通讯作者：
Kornblihtt, Alberto R.
影响因子：
4.5
作者：
Pandya-Jones, Amy;Bhatt, Dev M.;Black, Douglas L.
通讯作者：
Black, Douglas L.
影响因子：
16
作者：
Misteli, T;Spector, DL
通讯作者：
Spector, DL