选择性剪接顺式调控元件的位置效应
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摘要
人类基因组容量非常有限,仅3万多的基因数远远不能满足生物多样性和复杂性的要求。通过转录后调控网络,特别是选择性剪接的调控网络,有限的基因容量产生了庞大的蛋白质组复杂的表型。
对于选择性剪接调控的研究,一般着重于顺式作用元件的筛选和反式作用因子的筛选。本文的重点则于在讨论如下两个问题：
1顺式作用元件的强弱不但和其一级序列有关,和其所处的序列背景以及位置也有很重要的关系,即其功能是位置依赖的而不是长期以来认为的独立发生作用。
2mRNA在体内可能形成二级结构,并以此作为手段,对于位于其附近的顺式作用元件的功能进行调节。
人类转录组分析表明大于90%的基因存在选择性剪接,这说明了选择性剪接在产生蛋白质结构和功能的多样性中的重要作用(Nilsen and Graveley 2010)。前人的研究证明,对选择性剪接的调控多是通过反式作用元件(蛋白)结合于顺式作用元件之上,对剪接体组成部分的蛋白进行招募或者抑制达到调控目的的。在经典剪接调控理论中,pre-mRNA被认为是被hnRNP蛋白所包裹,强制形成单链状态。各种调控元件的功能强弱只与其一级序列有关,是背景独立的元件(context independent),可以在不同的外显子中独立发挥作用。
近年来,越来越多的例子证明,调控元件的独立性有相当大的相对性。元件和其所在的环境之间存在着精密的相互作用,这种相互作用对元件的功能调节作用非常大。有些元件甚至因为处于不同位置而发挥了完全相反的作用。但是对于这种被统称为位置效应(positional effect)的现象目前还没有进行比较系统的研究。单基因间的相关现象往往彼此矛盾,而造成这一效应的其机制更是众说纷纭。
通过建立不同的检测系统,我们将位置效应拆分成为三个方面进行了分别的讨论。
首先,我们发现各种剪接元件之间倾向于成簇协同发生作用。一旦远离了其他元件时,调控元件倾向于不发挥作用。结合不同蛋白的调控元件发生作用的位置略有不同,但大体上都是倾向集中于剪接位点附近。
其次,当存在西个5'剪接位点,竞争同一个3'剪接位点时,强的剪接位点往往会被选择。但是,剪接位点和其他元件间的相对位置有时会比剪接位点本身的强弱更为重要。上游的3'剪接位点可能对于下游5'剪接位点的选择具有调节的作用。
再次,mRNA上存在的二级结构可能对处于其内部或附近顺式作用元件的功能强弱具有决定性的调节作用。
There is a very limited number of genes in human genomic, thirty thousand genes. The large proteomic complexity is achieved by post-transcriptional mechanisms of gene regulation, especially by the network of alternative splicing.
The classic study of alternative splicing focused on selecting cis- and trans- factors. Our points in this paper are focused on the two below
1. The strength of the cis-elements is not only decided by the sequences of the elements but also interfered by the position and background it located
2. mRNA can form secondary structure in vivo, and regulate the function of the cis-element near it.
Over 90% of human gene was alternative spliced. In classic theory, pre-mRNA was transcribed and package with the hnRNPs to forced to be linear. Then the cis-elements on the mRNA were bound by the trans-factors and the components of splicesome were recruited to the splicing site and splice began. The strength of elements is context-independent, only related to the sequence of the elements itself.
Recently, more and more examples implied that the independence of the elements is rather limited. Elements interact with the background they located in a very precise way. In some cases, these interaction is so strong that element functioned in a rather different way on different positions. But till now, there is no systemic study on this positional effect. Data about this phenomena is both complex and puzzled.
Here we divided the phenomena into three parts, and studied them respectively.
Firstly, we found out the splicing signals (including all elements) worked in a clustered way. When located apart from other elements, the element tends to show no function. Functional position of different elements is diverse, but they all tend to clustered near the splicing site.
Secondly, when there are two competitive 5'splicing site, the stronger one will be chosen. But sometimes the distance between the splicing site and other splicing signals may be more important than the strength of the splicing site.
Thirdly, secondary structure on the pre-mRNA play an important role in the function of the element near it or inside it.
对于选择性剪接调控的研究,一般着重于顺式作用元件的筛选和反式作用因子的筛选。本文的重点则于在讨论如下两个问题：
1顺式作用元件的强弱不但和其一级序列有关,和其所处的序列背景以及位置也有很重要的关系,即其功能是位置依赖的而不是长期以来认为的独立发生作用。
2mRNA在体内可能形成二级结构,并以此作为手段,对于位于其附近的顺式作用元件的功能进行调节。
人类转录组分析表明大于90%的基因存在选择性剪接,这说明了选择性剪接在产生蛋白质结构和功能的多样性中的重要作用(Nilsen and Graveley 2010)。前人的研究证明,对选择性剪接的调控多是通过反式作用元件(蛋白)结合于顺式作用元件之上,对剪接体组成部分的蛋白进行招募或者抑制达到调控目的的。在经典剪接调控理论中,pre-mRNA被认为是被hnRNP蛋白所包裹,强制形成单链状态。各种调控元件的功能强弱只与其一级序列有关,是背景独立的元件(context independent),可以在不同的外显子中独立发挥作用。
近年来,越来越多的例子证明,调控元件的独立性有相当大的相对性。元件和其所在的环境之间存在着精密的相互作用,这种相互作用对元件的功能调节作用非常大。有些元件甚至因为处于不同位置而发挥了完全相反的作用。但是对于这种被统称为位置效应(positional effect)的现象目前还没有进行比较系统的研究。单基因间的相关现象往往彼此矛盾,而造成这一效应的其机制更是众说纷纭。
通过建立不同的检测系统,我们将位置效应拆分成为三个方面进行了分别的讨论。
首先,我们发现各种剪接元件之间倾向于成簇协同发生作用。一旦远离了其他元件时,调控元件倾向于不发挥作用。结合不同蛋白的调控元件发生作用的位置略有不同,但大体上都是倾向集中于剪接位点附近。
其次,当存在西个5'剪接位点,竞争同一个3'剪接位点时,强的剪接位点往往会被选择。但是,剪接位点和其他元件间的相对位置有时会比剪接位点本身的强弱更为重要。上游的3'剪接位点可能对于下游5'剪接位点的选择具有调节的作用。
再次,mRNA上存在的二级结构可能对处于其内部或附近顺式作用元件的功能强弱具有决定性的调节作用。
There is a very limited number of genes in human genomic, thirty thousand genes. The large proteomic complexity is achieved by post-transcriptional mechanisms of gene regulation, especially by the network of alternative splicing.
The classic study of alternative splicing focused on selecting cis- and trans- factors. Our points in this paper are focused on the two below
1. The strength of the cis-elements is not only decided by the sequences of the elements but also interfered by the position and background it located
2. mRNA can form secondary structure in vivo, and regulate the function of the cis-element near it.
Over 90% of human gene was alternative spliced. In classic theory, pre-mRNA was transcribed and package with the hnRNPs to forced to be linear. Then the cis-elements on the mRNA were bound by the trans-factors and the components of splicesome were recruited to the splicing site and splice began. The strength of elements is context-independent, only related to the sequence of the elements itself.
Recently, more and more examples implied that the independence of the elements is rather limited. Elements interact with the background they located in a very precise way. In some cases, these interaction is so strong that element functioned in a rather different way on different positions. But till now, there is no systemic study on this positional effect. Data about this phenomena is both complex and puzzled.
Here we divided the phenomena into three parts, and studied them respectively.
Firstly, we found out the splicing signals (including all elements) worked in a clustered way. When located apart from other elements, the element tends to show no function. Functional position of different elements is diverse, but they all tend to clustered near the splicing site.
Secondly, when there are two competitive 5'splicing site, the stronger one will be chosen. But sometimes the distance between the splicing site and other splicing signals may be more important than the strength of the splicing site.
Thirdly, secondary structure on the pre-mRNA play an important role in the function of the element near it or inside it.
引文
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2. Moore, M.J. and N.J. Proudfoot, Pre-mRNA processing reaches back to transcription and ahead to translation. Cell,2009.136(4):p.688-700.
3. Matlin, A.J., F. Clark, and C.W. Smith, Understanding alternative splicing:towards a cellular code. Nat Rev Mol Cell Biol,2005.6(5):p.386-98.
4. Grabowski, P.J. and D.L. Black, Alternative RNA splicing in the nervous system. Prog Neurobiol, 2001.65(3):p.289-308.
5. Cartegni, L., S.L. Chew, and A.R. Krainer, Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet,2002.3(4):p.285-98.
6. Caceres, J.F. and A.R. Kornblihtt, Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet,2002.18(4):p.186-93.
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