Role of structural dynamics in RNA regulation

结构动力学在 RNA 调控中的作用

• 批准号: 10685422
• 负责人: Anthony McDowell Mustoe
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685422
• 关键词: 3' Untranslated Regions; Area; Back; Base Pairing; Binding; Binding Sites; Biology; Cells; Chemicals; Complex; Data; Disease; Distal; Gene Expression; Instruction; Lesion; Link; Maps; Medicine; Messenger RNA; MicroRNAs; Modeling; Molecular; Mutation; Play; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Research; Resolution; Role; Site; Structure; Technology; Translations; Untranslated Regions; Work; biophysical techniques; combinatorial; design; human disease; improved; insight; molecular targeted therapies; next generation; single molecule; therapeutic target; 3' Untranslated Regions; Area; Back; Base Pairing; Binding; Binding Sites; Biology; Cells; Chemicals; Complex; Data; Disease; Distal; Gene Expression; Instruction; Lesion; Link; Maps; Medicine; Messenger RNA; MicroRNAs; Modeling; Molecular; Mutation; Play; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Research; Resolution; Role; Site; Structure; Technology; Translations; Untranslated Regions; Work; biophysical techniques; combinatorial; design; human disease; improved; insight; molecular targeted therapies; next generation; single molecule; therapeutic target

Project Summary Messenger RNAs (mRNAs) encode complex regulatory instructions in their 3' untranslated regions (3'UTRs) that prescribe context-dependent control of translation and decay. Disruption of mRNA post-transcriptional regulation by mutational lesions or shortening of 3'UTRs has been linked to diverse human diseases. RNA molecules fold back on themselves into base-paired secondary structures and occasionally higher-order tertiary structures, and sequence-encoded structures are hypothesized to play key roles in directing 3'UTR regulation. For example, RNA structures can provide specific binding sites for RNA binding proteins and may tune the accessibility of microRNA target sites. RNA structures may also function as molecular switches, with protein or microRNA binding triggering specific 3'UTR structural changes that alter the activity of distal regulatory sites. However, little remains known about 3'UTR structures and their role in post-transcriptional regulation. Existing data indicate that 3'UTRs have heterogenous and dynamic structures, which makes them challenging to study by traditional chemical probing or biophysical methods. My research group has recently developed a new single-molecule chemical probing technology (DANCE-MaP) that makes it possible to accurately define RNA structural ensembles consisting of 2-3 coexisting states in living cells. We will pursue two areas of research that exploit and build on the DANCE-MaP technology: (1) We will apply DANCE- MaP to define 3'UTR folding landscapes and mechanisms of combinatorial regulation by RNA binding proteins and microRNAs. (2) We will develop next-generation technologies that can resolve structurally heterogenous RNAs with greater resolution and provide model-free, physical interpretation of chemical probing data. This work will provide an improved understanding of mRNA regulatory mechanisms, helping advance efforts to therapeutically target 3'UTRs to modulate gene expression, and contribute new structure determination technologies that will be of broad utility to the RNA biology field.

项目摘要 Messenger RNA（mRNA）在其3'未翻译中编码复杂的调节说明 规定对翻译和衰减的上下文控制的区域（3'UTRS）。破坏 通过突变病变或3'UTRS缩短的转录后调控mRNA 与多样化的人类疾病有关。 RNA分子向后折叠成碱 二级结构和偶尔高阶三级结构，并编码序列 假设结构在指导3'UTR调节中起关键作用。例如，RNA 结构可以为RNA结合蛋白提供特定的结合位点，并可能调整 MicroRNA目标站点的可访问性。 RNA结构也可能充当分子开关， 蛋白质或microRNA结合触发特定的3'UTR结构变化，改变了 远端调节位点的活性。但是，关于3'UTR结构及其它们的 在转录后调节中的作用。现有数据表明3'Utrs具有异质和 动态结构，这使他们具有挑战性地通过传统的化学探测或 生物物理方法。我的研究小组最近开发了一种新的单分子 化学探测技术（舞蹈图），可以准确定义RNA 结构合奏由活细胞中的2-3个共存状态组成。我们将追求两个领域 利用和基于舞蹈地图技术的研究：（1）我们将应用舞蹈 - 定义RNA组合调节的3'UTR折叠景观和机制 结合蛋白和microRNA。 （2）我们将开发下一代技术 解决结构上的异源RNA，并提供更大的分辨率，并提供无模型的物理 化学探测数据的解释。这项工作将提供对 mRNA调节机制，有助于促进治疗方法将3'utrs靶向 调节基因表达，并贡献新的结构测定技术 RNA生物学领域的广泛实用性。