可变剪接相关生物大分子相互作用网络的构建与分析

As we delve deeper into the regulation of alternative splicing, it is becoming clear that the control of splice site choice is far more complex than anticipated. Classically, attempts to understand the mechanism and regulation of alternative splicing have focused on the cis-acting elements and trans-acting protein splicing factors that facilitate and regulate the exon recongnition. More and more works indicated that neither the cis- nor trans-elements are sufficient to indentify intron and exon accurately, implying that there are additional regulatory layers providing additional information, remaining to be discovered.Comprehending alternative splicing requires a understanding of the regulation network of protein-protein, protein-DNA，protein-RNA interactions, and epigenetic information including histone modification, nucleosome positioning, chromatin remodelling etc. Spliceosome recognise different splice sites in pre-mRNA to produce many splicing variants. In metazoans, alternative splicing plays an important role in generating different protein products that function in diverse cellular processes,including cell growth, tissue-specific differentiation and death. Based on previous experiment works, this project will construct biological macromolecule interaction database associated with alternative splicing by using bioinformatics methods, and then construct biological macromolecule interaction networks by using Cytoscape software. After that, we would like to understand structure and mechanism of epigenetic networks as following: 1、analyzing topologic strcuture of network, for example conservation motifs. 2、analyzing the relation between epigenetic factors and alternative splicing.3、pay an attention on mechanism of epigenetic network associated with alternative splicing, finding new "epigenetic factors-protein adaptor-RNA" splicing systems. We will pay more attention on interaction mechanism of genetic coding information networks and epigenetic information networks associated with alternative splicing. It is a new way to understand the mechanism of alternative splicing and regulation of gene expression.

剪接顺式元件或反式因子等信号远不足以精确区分内含子与外显子，在诸多与环境有关的表观遗传信息控制下，通过复杂的蛋白质、DNA及RNA相互作用网络，剪接体最终识别mRNA前体的不同位点产生了多种剪接变体，进而引起细胞的组织特异性分化、个体发育乃至疾病发生。本项目拟采用生物信息学方法，系统整理现有实验工作，建立可变剪接相关生物大分子相互作用数据库；然后基于Cytoscape平台构建可变剪接相关生物大分子相互作用网络；进而从以下几个方面理解表观遗传信息网络的组成与运行机制：①、分析网络保守模体等拓扑结构性质；②、分析各类表观遗传学因素与可变剪接关系的规律；③、关注可变剪接相关表观遗传因素的相互作用机制，发现新的"表观遗传因素-蛋白质适配器-RNA"可变剪接系统。项目探索可变剪接相关遗传编码信息和表观遗传信息网络及交互作用机制，为可变剪接乃至基因表达调控机制的理解提供新思路。

剪接顺式元件或反式因子等信号远不足以精确区分内含子与外显子，在诸多与环境有关的表观遗传信息控制下，通过复杂的蛋白质、DNA 及RNA 相互作用网络，剪接体最.终识别mRNA 前体的不同位点产生了多种剪接变体，进而引起细胞的组织特异性分化、个体发育乃至疾病发生。项目探索可变剪接相关遗传编码信息和表观遗传信息网络及交互作用机制，为可变剪接乃至基因表达调控机制的理解提供新思路。.①、完成“可变剪接相关生物大分子相互作用数据库（MiasDB）”的构建工作，这个数据库是在互作网络层面研究可变剪接机制的重要资源；.②、对12个基因构建可变剪接相关大分子相互作用网络，尝试从相互作用网络层面理解基因可变剪接的分子机制；.③、以人心肌细胞为模型，Ⅰ型神经纤维瘤基因NF1为对象，解释了从细胞外环境诱导，到信号跨细胞膜，影响Ca离子内流，导致去乙酰化酶外流，影响染色质结构并调控RNA聚合酶II移动速率，最终导致可变外显子跳跃的分子机制。

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