生物谷報(bào)道：基因組測(cè)序計(jì)劃的一個(gè)驚人的發(fā)現(xiàn)就是人類(lèi)所具有的蛋白質(zhì)編碼基因的數(shù)量與明顯較為簡(jiǎn)單的線蟲(chóng)的數(shù)量相似。顯然,，有基因以外的其他東西導(dǎo)致了較簡(jiǎn)單和較為復(fù)雜生命形式之間的遺傳差異,。
增加的功能和細(xì)胞復(fù)雜性大部分能夠由基因和基因產(chǎn)物如何被調(diào)節(jié)來(lái)解釋。現(xiàn)在,，來(lái)自多倫多大學(xué)的研究人員在最新一期的Genome Biology雜志上發(fā)表的文章揭示出基因表達(dá)過(guò)程中的選擇性拼接以一個(gè)細(xì)胞和組織特異性方式被調(diào)節(jié)的強(qiáng)度比之前認(rèn)為的要高,，并且這種調(diào)節(jié)很多是發(fā)生在神經(jīng)系統(tǒng)中的。這種選擇性拼接步驟能使一個(gè)單獨(dú)的基因通過(guò)加工RNA專(zhuān)欄本獲得多種蛋白質(zhì)產(chǎn)物,。
多倫多大學(xué)的Benjamin Blencowe教授領(lǐng)導(dǎo)的研究組發(fā)現(xiàn),，與其他哺乳動(dòng)物組織相比，神經(jīng)系統(tǒng)組織中的相同生物學(xué)過(guò)程和途徑中起作用的相當(dāng)一部分基因是受到選擇性拼接調(diào)節(jié)的,。
Blencowe教授解釋說(shuō),，最有趣的是許多基因在身體系統(tǒng)中具有重要且特殊的功能，其中包括與記憶和學(xué)習(xí)有關(guān)的功能,。但是,，在大多數(shù)情況下，研究這些基因的研究人員都沒(méi)有意識(shí)到他們研究的基因在拼接水平上被調(diào)節(jié),。Blencowe相信,，他的研究組獲得的數(shù)據(jù)為了解基因在不同的身體部位起到不同作用的分子機(jī)制奠定一定的基礎(chǔ)。
Blencowe將這些發(fā)現(xiàn)部分歸功于使用了一種由研究組在幾年前改良的強(qiáng)大的工具,。這種工具包含了基因芯片和計(jì)算機(jī)程序,，使研究人員能夠同時(shí)測(cè)量細(xì)胞和組織中成千上萬(wàn)個(gè)選擇性拼接。研究人員表示,，只是到了近期,，研究人員才開(kāi)始在基因水平上研究選擇性拼接。多倫多的研究人員現(xiàn)在已經(jīng)能夠得到整體水平上的基因調(diào)節(jié)圖譜,。
選擇性拼接(alternative splicing)是一種常見(jiàn)的真核生物前體mRNA (pre-mRNA)轉(zhuǎn)錄后加工的方法,，這是真核生物細(xì)胞在基因表達(dá)上的一項(xiàng)重要步驟：將pre-mRNA產(chǎn)物中的introns剪除，再將exons編接起來(lái)以產(chǎn)生可以轉(zhuǎn)譯出蛋白的mRNA,。
此前,，在7月1日的G&D（Gene & Development）雜志上，來(lái)自美國(guó)加州大學(xué)洛杉磯分校的Douglas Black博士和同事詳細(xì)描述了神經(jīng)元發(fā)育過(guò)程中選擇性拼接如何被調(diào)節(jié)重新編排,。
已經(jīng)知道,，多嘧啶序列結(jié)合蛋白(polypyrimidine tract binding protein，PTB)是多種細(xì)胞類(lèi)型中選擇性拼接過(guò)程的一個(gè)抑制劑,。而神經(jīng)元中的PTB版本即nPTB是一種只在神經(jīng)細(xì)胞中表達(dá),。但是此前并不清楚它的功能,。
現(xiàn)在，Black博士和同事證明在神經(jīng)元發(fā)育過(guò)程中,，聯(lián)通PTB和nPTB的一個(gè)開(kāi)關(guān)能誘導(dǎo)大量選擇性拼接模式發(fā)生改變,。
這種PTB蛋白質(zhì)中的開(kāi)關(guān)所導(dǎo)致的拼接重排又增加了確定有絲分裂神經(jīng)元功能的遺傳“變數(shù)”。
原始出處：
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
Background
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.
