The search for alternative splicing regulators: new approaches offer a path to a splicing code
The search for alternative splicing regulators: new approaches offer a path to a splicing code
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DOI：
10.1101/gad.1643108
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发表时间：
2008-02-01
影响因子：
10.5
通讯作者：
Manley, James L.
中科院分区：
文献类型：
--
作者：
David, Charles J.;Manley, James L.
复杂的多细胞生物体需要一组不同的蛋白质来设置专门细胞类型的形式和功能。完整基因组序列的可用性已经揭示，与单细胞生物相比，蛋白质编码基因的数量没有大幅增加，而是更复杂的真核生物通过选择性剪接（AS）过程从相对有限数量的基因中获得更多的多样性。AS导致由给定基因产生的mRNA组成的细胞类型、发育阶段、性别或信号调节的变化，这是由剪接位点选择的变化引起的（Black 2003; Matlin et al. 2005）。存在许多不同类型的AS事件，从组织特异性包含盒式外显子到果蝇中的Dscam基因，Dscam基因包含四个外显子簇，包含12、48、33和2个互斥变体，这是AS复杂性的一个极端例子（Bharadwaj和Kolodkin 2006）。此外，从相对较少的AS事件中可以清楚地看出，AS的调节有多种形式，这将在本文后面更详细地讨论。最后，AS的功能结果差异很大，从有效地关闭基因（例如，包含含有提前终止密码子的外显子的结果）到蛋白质功能的微妙变化，尽管如此复杂，但从细胞类型中调节AS的因子的表达和调节的变化来理解AS模式变化的目标似乎是可以实现的。这部分是因为最近的技术进步使我们能够从单个剪接因子开始，确定其在AS调控中的全基因组作用。然而，如果没有完整的AS调节器列表，确定AS细胞代码的雄心勃勃的目标将不可能实现，目前没有理由相信我们在任何后生动物中接近完成这样的列表。黑柳等人（2006）最近在秀丽隐杆线虫中开发了一个系统，该系统允许
Complex multicellular organisms require a diverse set of proteins to set the form and function of specialized cell types. The availability of complete genomic sequences has revealed that instead of a large increase in the number of protein coding genes compared with unicellular organisms, more complex eukaryotes instead obtain more diversity out of a relatively limited number of genes through the process of alternative splicing (AS). AS results in the cell type-, developmental stage-, sex-, or signal-regulated changes in composition of an mRNA produced from a given gene, brought about by changes in splice site choice (Black 2003; Matlin et al. 2005). There are many different types of AS events, ranging from the tissue-specific inclusion of a cassette exon to the Dscam gene in Drosophila, which contains four clusters of exons containing 12, 48, 33, and 2 mutually exclusive variants, an extreme example of AS complexity (Bharadwaj and Kolodkin 2006). Additionally, it is clear from the relatively small number of AS events that have been studied extensively at a mechanistic level that regulation of AS takes many forms, as will be discussed in more detail later in this article. Lastly, the functional outcomes of AS vary greatly, from effectively turning off a gene (the result of including an exon containing a premature stop codon, for example), to a subtle change in a protein’s function.In spite of this complexity, the goal of understanding the changes in AS patterns in terms of changes in expression and regulation of factors that regulate AS across cell types appears achievable. This is in part because recent technical advances allow us, starting with an individual splicing factor, to determine its genome-wide role in AS regulation. However, the ambitious goal of determining a cellular code for AS will be impossible to realize without a complete list of AS regulators, and currently there is no reason to believe we are anywhere near completing such a list in any metazoan. Kuroyanagi et al.(2006) have developed recently a system in Caenorhabditis elegans, which allows for the