Computational biology of regulation by small RNAs

基因沉默和由小RNA引导的其他调控过程是已知的生物控制机制的重要补充。小RNA基因产物的总数和生物学功能在很大程度上仍不清楚，特别是在哺乳动物中。根据最近的实验和预测，有可能比迄今发现的非编码RNA要多得多，这些RNA可能参与调控 转录、剪接、翻译和染色质修饰。因此，发现小RNA的互补性、其生物学功能及其对疾病的影响是分子细胞生物学的重要目标。我们的总体目标是帮助解开小RNA调控的分子细节，重点是哺乳动物，并开发工具来预测这种调控的功能影响。我们将使用计算手段，包括算法、软件、数据库和完整的基因组序列，与我们合作者的实验实验室密切合作。我们将从系统和广泛的小RNA图谱的实验捕获以及小RNA的目标基因的检测和验证开始。然后，我们计划将小RNA及其调控目标置于已知途径的背景下，提供丰富的统一网络信息资源。利用这一资源，我们将(I)分析 并预测小RNA、它们的控制区和它们的靶点变化的后果，(Ii)促进重点验证实验的设计，以及(Iii)为临床应用的发展奠定基础。具体的研究领域将是免疫系统和2型糖尿病。在这项研究的过程中，我们将构建详细的小RNA调控网络和相关的生物效应，包括：小RNA生产的转录控制，通过转录抑制或转录产物降解而导致的基因沉默，以及染色质修饰。我们建议在哺乳动物细胞中关于基因、蛋白质、相互作用和反应的结构化途径数据的不断增长的语料库的背景下组织和分析这些信息。对于每个具体目标，我们将通过在公共领域提供软件和信息资源，促进方案项目成果的传播和应用。 具体目标： A)图谱：为哺乳动物细胞的小RNA图谱建立数据注释管道，b)靶标：开发识别和验证小RNA功能靶标的计算方法。C)网络：构建涉及小RNA的调控网络，d)功能：分析小RNA的功能和遗传变异的后果。

Gene silencing and other regulatory processes guided by small RNAs are important additions to the known repertoire of biological control mechanisms. Both the total number and biological function of small RNA gene products are still largely unknown, especially in mammals. It is plausible, based on recent experiments and predictions, that there are many more non-coding RNAs than have been discovered to date and that these may be involved in regulating transcription, splicing, translation, and chromatin modification. Discovery of the complement of small RNAs, their biological functions and disease implications is therefore an important aim in molecular cell biology. Our overall aim is to help unravel the molecular details of regulatory control by small RNAs, with focus on mammals, and to develop tools for the prediction of the functional effects of this control. We will use computational means, including algorithms, software, databases and complete genome sequences, working closely with the experimental laboratories of our collaborators. We will start with the systematic and broad experimental capture of small RNA profiles and the detection and validation of target genes of small RNAs. We then plan to put small RNAs and their regulatory targets into the context of known pathways, providing a rich unified network information resource. Using this resource we will (i) analyze and predict the consequences of changes in small RNAs, their control regions and their targets, (ii) facilitate the design of focussed validation experiments and (iii) lay the foundations for the development of clinical applications. Specific areas of investigation will be the immune system and type 2 diabetes. During the course of this research, we will construct detailed regulatory networks of small RNAs and associated biological effects including: transcriptional control of small RNA production, gene silencing by translational inhibition or degradation of transcripts, and chromatin modification. We propose to organize and analyze this information in the context of the growing corpus of structured pathway data for genes, proteins, interactions and reactions in mammalian cells. For each of the specific aims we will facilitate dissemination and application of the results of the program project by making available in the public domain both software and information resources. Specific Aims: a) Profiles: Build a data annotation pipeline for small RNA profiling of mammalian cells, b) Targets: Develop computational methods for the identification and validation of the functional targets of small RNAs. c) Networks: Construct regulatory networks involving small RNAs, d) Function: Analyze the function of small RNAs and the consequences of genetic variation.