Evolution of Nova-dependent splicing regulation in the brain.
Evolution of Nova-dependent splicing regulation in the brain.
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大脑中NOVA依赖性剪接调节的演变。
DOI：
10.1371/journal.pgen.0030173
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发表时间：
2007-10
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
大量的替代外显子与组织特异性模式拼接，但对这些模式如何进化知之甚少。在这里，我们研究了神经元特异性剪接因子Nova1和Nova2的保守性，以及它们在小鼠大脑中调节的可变剪接外显子。而诺瓦RNA结合域是94%相同的脊椎动物物种，诺瓦依赖的剪接沉默子和增强子元件（YCAY集群）显示出更大的分歧，小于50%的小鼠YCAY集群是保守的，在斑马鱼基因组中的邻位。为了研究组织特异性剪接的进化与YCAY簇之间的关系，我们比较了斑马鱼、鸡和小鼠的Nova调控外显子的脑特异性剪接。YCAY簇在低等脊椎动物中的存在总是预测跨物种脑特异性剪接的保守性，而它们在低等脊椎动物中的缺失与选择性剪接的丧失相关。我们推测，进化诺瓦调节剪接在高等脊椎动物的收益主要是通过顺式作用元件的变化，组织特异性剪接可能在某些情况下演变在一个单一的步骤对应的YCAY簇的进化，和YCAY簇的保守水平涉及的功能编码的调节RNA。选择性剪接从单个基因产生不同的mRNA亚型，从而增加细胞可以产生的蛋白质数量。这在大脑中尤其重要，因为大脑拥有许多脑特异性剪接因子。在这项研究中，我们研究了一个这样的因子Nova对大脑特异性剪接调控的进化。先前的研究已经确定了小鼠大脑中由Nova调控的约100个替代外显子。我们发现Nova蛋白序列在脊椎动物从鱼类进化到人类的过程中几乎没有变化，而RNA靶标本身则发生了显着的进化。有趣的是，在大多数情况下，RNA转录物中保守的Nova结合元件的存在与脑特异性剪接的保守性相关。此外，Nova依赖性剪接的进化涉及由靶RNA编码的功能，使得编码核心作用（如突触粘附、离子通道和细胞骨架蛋白）的RNA的Nova调节的剪接平均比编码调节作用（如跨膜受体和信号转导蛋白）的RNA的剪接更保守。
A large number of alternative exons are spliced with tissue-specific patterns, but little is known about how such patterns have evolved. Here, we study the conservation of the neuron-specific splicing factors Nova1 and Nova2 and of the alternatively spliced exons they regulate in mouse brain. Whereas Nova RNA binding domains are 94% identical across vertebrate species, Nova-dependent splicing silencer and enhancer elements (YCAY clusters) show much greater divergence, as less than 50% of mouse YCAY clusters are conserved at orthologous positions in the zebrafish genome. To study the relation between the evolution of tissue-specific splicing and YCAY clusters, we compared the brain-specific splicing of Nova-regulated exons in zebrafish, chicken, and mouse. The presence of YCAY clusters in lower vertebrates invariably predicted conservation of brain-specific splicing across species, whereas their absence in lower vertebrates correlated with a loss of alternative splicing. We hypothesize that evolution of Nova-regulated splicing in higher vertebrates proceeds mainly through changes in cis-acting elements, that tissue-specific splicing might in some cases evolve in a single step corresponding to evolution of a YCAY cluster, and that the conservation level of YCAY clusters relates to the functions encoded by the regulated RNAs. Alternative splicing generates different mRNA isoforms from a single gene and thus increases the number of proteins a cell can produce. This is particularly important in the brain, which possesses a number of brain-specific splicing factors. In this study, we have looked at evolution of brain-specific splicing regulation by one such factor, Nova. Previous studies have identified ∼100 alternative exons that are regulated by Nova in mouse brain. We find that the Nova protein sequence changed little during vertebrate evolution from fish to human, whereas the RNA targets themselves have evolved significantly. Interestingly, the presence of conserved Nova binding elements in an RNA transcript in most cases correlates with conservation of brain-specific splicing. In addition, the evolution of Nova-dependent splicing relates to the functions encoded by the target RNAs, such that Nova-regulated splicing of RNAs encoding core roles such as synaptic adhesion, ion channel, and cytoskeletal proteins is on average more conserved than splicing of the RNAs encoding regulatory roles, such as transmembrane receptor and signal transduction proteins.