Genome Biology：基因表达过程中选择性拼接的复杂性
生物谷报道：基因组测序计划的一个惊人的发现就是人类所具有的蛋白质编码基因的数量与明显较为简单的线虫的数量相似。显然，有基因以外的其他东西导致了较简单和较为复杂生命形式之间的遗传差异。
增加的功能和细胞复杂性大部分能够由基因和基因产物如何被调节来解释。现在，来自多伦多大学的研究人员在最新一期的Genome Biology杂志上发表的文章揭示出基因表达过程中的选择性拼接以一个细胞和组织特异性方式被调节的强度比之前认为的要高，并且这种调节很多是发生在神经系统中的。这种选择性拼接步骤能使一个单独的基因通过加工RNA专栏本获得多种蛋白质产物。
多伦多大学的Benjamin Blencowe教授领导的研究组发现，与其他哺乳动物组织相比，神经系统组织中的相同生物学过程和途径中起作用的相当一部分基因是受到选择性拼接调节的。
Blencowe教授解释说，最有趣的是许多基因在身体系统中具有重要且特殊的功能，其中包括与记忆和学习有关的功能。但是，在大多数情况下，研究这些基因的研究人员都没有意识到他们研究的基因在拼接水平上被调节。Blencowe相信，他的研究组获得的数据为了解基因在不同的身体部位起到不同作用的分子机制奠定一定的基础。
Blencowe将这些发现部分归功于使用了一种由研究组在几年前改良的强大的工具。这种工具包含了基因芯片和计算机程序，使研究人员能够同时测量细胞和组织中成千上万个选择性拼接。研究人员表示，只是到了近期，研究人员才开始在基因水平上研究选择性拼接。多伦多的研究人员现在已经能够得到整体水平上的基因调节图谱。
选择性拼接(alternative splicing)是一种常见的真核生物前体mRNA (pre-mRNA)转录后加工的方法，这是真核生物细胞在基因表达上的一项重要步骤：将pre-mRNA产物中的introns剪除，再将exons编接起来以产生可以转译出蛋白的mRNA。
此前，在7月1日的G&D（Gene & Development）杂志上，来自美国加州大学洛杉矶分校的Douglas Black博士和同事详细描述了神经元发育过程中选择性拼接如何被调节重新编排。
已经知道，多嘧啶序列结合蛋白(polypyrimidine tract binding protein，PTB)是多种细胞类型中选择性拼接过程的一个抑制剂。而神经元中的PTB版本即nPTB是一种只在神经细胞中表达。但是此前并不清楚它的功能。
现在，Black博士和同事证明在神经元发育过程中，联通PTB和nPTB的一个开关能诱导大量选择性拼接模式发生改变。
这种PTB蛋白质中的开关所导致的拼接重排又增加了确定有丝分裂神经元功能的遗传“变数”。
原始出处：
Genome Biology 2007, 8:R108 doi:10.1186/gb-2007-8-6-r108
| Published | 12 June 2007 |
Subject areas: Neurobiology, Molecular biology, Bioinformatics, Genome studies
Functional coordination of alternative splicing in the mammalian central nervous system
Matthew Fagnani* 1 ,2 
, Yoseph Barash* 1 ,3 , Joanna Y Ip1 ,2 , Christine Misquitta1 , Qun Pan1 , Arneet L Saltzman1 ,2 , Ofer Shai3 , Leo Lee3 , Aviad Rozenhek4 , Naveed Mohammad2 , Sandrine Willaime-Morawek2 , Tomas Babak1 ,2 , Wen Zhang1 ,2 , Timothy R Hughes1 ,2 , Derek van der Kooy2 , Brendan J Frey1 ,3 
and Benjamin J Blencowe1 ,2
1Banting and Best Department of Medical Research, Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario, Canada. M5S 3E1
2Department of Molecular and Medical Genetics, Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario, Canada. M5S 3E1
3Department of Electrical and Computer Engineering, University of Toronto, 40 St. George's Street, Toronto, Ontario, Canada
4School of Computer Science and Engineering, Hebrew University, Jerusalem 91904, Israel
Abstract
Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood.
Results
Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues.
Conclusion
Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS.
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