Center for Cell and Virus Theory, Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
J Theor Biol. 2010 Apr 21;263(4):471-80. doi: 10.1016/j.jtbi.2009.12.025. Epub 2010 Jan 5.
Pre-mRNA alternative splicing (AS) allows individual genes to produce multiple types of mRNA and associated protein isoforms. While AS regulation enables the production of the hundreds of thousands of types of proteins needed for the normal functioning of the human cell, it also presents many opportunities for the onset of cancer and other diseases. The AS process is known to be regulated by a group of serine/arginine rich (SR) proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), and small nuclear ribonucleoprotein (snRNP) particles through a complex assembly. Each gene-exon is regulated by one or multiple splicing regulators, from which one may hypothesize the existence of an alternative splicing regulatory network (SRN). The SRN contains a list of gene-exons, for each of which the factors that up/down regulate them are provided. Since defects in the SRN play key roles in human disease, a reconstruction of human SRN could be used to facilitate the design of diagnostic and therapeutic strategies. In this paper, we present a methodology to automate genome-wide SRN reconstruction. We construct SRN based on an extensive correlation analysis of human exon expression microarray data, conventional gene expression microarray profiles, and an experimentally verified AS and transcriptional regulatory interaction training set. This SRN reconstruction methodology is demonstrated and software (AutoNet) that automates the reconstruction of SRN is developed. A genome-wide SRN was constructed for normal human cells and an assessment of the reliability of each predicted interaction is provided. Human SRN we constructed are free available from our web portal: https://ruby.chem.indiana.edu/scorenfl/srn_results/lookup0.php.
前体 mRNA 可变剪接 (AS) 允许单个基因产生多种类型的 mRNA 和相关的蛋白质同工型。虽然 AS 调控使人类细胞正常功能所需的数十万种蛋白质的产生成为可能，但它也为癌症和其他疾病的发生提供了许多机会。已知 AS 过程受到一组丝氨酸/精氨酸丰富 (SR) 蛋白、异质核核糖核蛋白 (hnRNPs) 和小核核糖核蛋白 (snRNP) 颗粒的调控，通过复杂的组装。每个基因外显子都受到一个或多个剪接调控因子的调控，从中可以假设存在一个可变剪接调控网络 (SRN)。SRN 包含一个基因外显子列表，其中为每个基因外显子提供了上调/下调它们的因子。由于 SRN 中的缺陷在人类疾病中起着关键作用，因此重建人类 SRN 可用于促进诊断和治疗策略的设计。在本文中，我们提出了一种自动化全基因组 SRN 重建的方法。我们基于人类外显子表达微阵列数据、常规基因表达微阵列图谱以及经过实验验证的 AS 和转录调控相互作用训练集的广泛相关性分析来构建 SRN。展示了这种 SRN 重建方法，并开发了自动重建 SRN 的软件 (AutoNet)。为正常人类细胞构建了全基因组 SRN，并提供了对每个预测相互作用的可靠性的评估。我们构建的人类 SRN 可从我们的网络门户免费获得：https://ruby.chem.indiana.edu/scorenfl/srn_results/lookup0.php。
