San Diego Center for Systems Biology (SDCSB), University of California, San Diego, La Jolla, CA 92093, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Nucleic Acids Res. 2018 Nov 16;46(20):10598-10607. doi: 10.1093/nar/gky870.
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.
剪接体催化前信使 RNA（mRNA）中内含子的去除，以及随后外显子与高度保真的配对。某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的 mRNA 中（盒式外显子），从而促进了人类蛋白质组的多样化。有趣的是，剪接是在转录过程中启动的（有时甚至完成）。在这里，我们开发了一个动力学数学建模框架来研究替代的共转录剪接（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转录后剪接时更有可能，并且某些外显子比其他外显子更有可能是可调节的（即盒式外显子），这基于外显子-内含子结构的上下文。对于这种可调节的外显子，转录延伸率可能会影响剪接结果。在 CTS 范式中，我们研究了短内含子（即“内含子定义”）或短外显子（即“外显子定义”）之间剪接位点的先前描述的协同作用假说，并发现分别编码这些假说的模型忠实地再现了果蝇和人类基因组中的观察结果。
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