Combinatorial RNA Structural Features That Control RNA-Protein Binding

控制 RNA-蛋白质结合的组合 RNA 结构特征

• 批准号: 8619709
• 负责人: Jeffrey Hsu-Min Chuang
• 金额: $ 23.63万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-25 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619709
• 关键词: Accounting; Base Sequence; Binding; Binding Sites; Bioinformatics; Biological Assay; Collaborations; Collection; Communities; Computing Methodologies; DNA-Protein Interaction; Data; Data Set; Disease; Electrophoretic Mobility Shift Assay; Elements; Fragile X Syndrome; Gel; Gene Expression Regulation; Health; High-Throughput Nucleotide Sequencing; Human; In Vitro; Indium; Individual; Joints; Lead; Learning; Logic; Malignant Neoplasms; Measurement; Methods; Modeling; Muscular Dystrophies; Play; Prader-Willi Syndrome; Problem Solving; Process; Protein Binding; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Research Personnel; Resources; Retinitis Pigmentosa; Role; Software Tools; Spinal Muscular Atrophy; Structure; Testing; Transcript; Translations; Validation; base; combinatorial; human disease; innovation; insight; markov model; meetings; novel; public health relevance; research study; sequence learning

PROJECT SUMMARY/ABSTRACT RNA-protein binding is critical to gene regulation, controlling fundamental processes including RNA splicing, translation, localization and stability. RNA-protein interactions play a role in a wide variety of diseases including muscular dystrophy, fragile X syndrome, mental retardation, Prader-Willi syndrome, retinitis pigmentosa, spinal muscular atrophy, and cancer. Advances towards understanding the underlying mechanisms of RNA-protein interaction have great value for improvement of human health. While most studies of gene regulation have focused on DNA- protein interactions, the mechanisms by which RNA-binding proteins (RBPs) act remain enigmatic. However, new high-throughput measurements will soon yield vast amounts of RNA- protein interaction data. These could dramatically clarify RNA regulation, but also demand novel analytical approaches. To meet this challenge, we propose novel computational methods to determine sequences and structures critical to RNA-protein binding, based on hundreds of CLIP-seq and SELEX datasets now being generated for the human ENCODE project. Current methods for modeling RNA-protein interactions have low predictive power, which we hypothesize is due, mainly, to two different issues: (a) they ignore combinatorial binding of multiple elements within each RNA to the protein, and (b) they only account for structure in a superficial manner. We will solve these problems by developing innovative methods that use complementary CLIP-seq and SELEX data to: determine the different classes of RNA elements binding each RBP; learn the combinatorial logic among classes; and learn the sequences and structures that define each class. We will additionally validate our methods for at least two RBPs using RNA-protein gel shift experiments. We expect that this exploratory study will yield powerful, experimentally validated software tools to determine combinatorial and structural aspects of RNA-protein binding from high-throughput sequencing data. !

项目摘要/摘要 RNA-蛋白质结合是基因调控的关键，控制的基本过程包括 RNA剪接、翻译、定位和稳定性。RNA-蛋白质相互作用在广泛的 各种疾病，包括肌肉营养不良，脆性X综合征，智力低下， Prader-Willi综合征、视网膜色素变性、脊髓性肌萎缩症和癌症。预付款 对于理解RNA-蛋白质相互作用的潜在机制具有重要的价值 为了改善人类健康。虽然大多数关于基因调控的研究都集中在DNA上- 蛋白质相互作用，RNA结合蛋白(RBPs)的作用机制仍然存在 神秘莫测。然而，新的高通量测量很快就会产生大量的RNA- 蛋白质相互作用数据。这些可以极大地阐明RNA的调控，但也需要新奇的东西 分析方法。为了迎接这一挑战，我们提出了新的计算方法来 确定对RNA-蛋白质结合至关重要的序列和结构，基于数百 目前正在为人类ENCODE项目生成CLIP-SEQ和SELEX数据集。当前 建模RNA-蛋白质相互作用的方法预测能力较低，这是我们 假设主要是由于两个不同的问题：(A)它们忽略了 每个RNA中的多个元素与蛋白质有关，以及(B)它们只解释a中的结构 肤浅的态度。我们将通过开发创新方法来解决这些问题，这些方法使用 互补的CLIP-SEQ和SELEX数据：确定不同类别的RNA元素 绑定每个RBP；学习类之间的组合逻辑；学习序列和 定义每个类的结构。我们还将对至少两个RBP验证我们的方法 采用RNA-蛋白质凝胶移位实验。我们期待这项探索性研究将产生 强大的、经过实验验证的软件工具，用于确定组合和结构 来自高通量测序数据的RNA-蛋白质结合的方面。 好了！