Integrated Studies of 3'-UTR Mediated Gene Regulation

3-UTR介导的基因调控的综合研究

• 批准号: 7448484
• 负责人: JOEL H GRABER
• 金额: $ 24.47万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448484
• 关键词: 3' Untranslated Regions; Animal Model; Base Sequence; Biological Process; Cell division; Characteristics; Class; Collaborations; Communities; Complementary DNA; Complex; Computer Analysis; Computer software; Condition; DNA; Databases; Development; Disease; Elements; Embryo; Embryonic Development; Expressed Sequence Tags; Fertilization; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genie; Genome; Genomics; Growth; Health; Histocompatibility Testing; Informatics; Life; Location; Mediating; Messenger RNA; Methodology; Modeling; Mutation; Oogenesis; Organism; Orthologous Gene; Pattern; Polyadenylation; Polyadenylation Pathway; Positioning Attribute; Post-Transcriptional Regulation; Process; Proteins; Public Health; RNA Splicing; Rana; Range; Regulation; Regulatory Element; Reproduction; Resources; Scientist; Site; Spermatogenesis; Staging; Statistically Significant; Structure; System; Testing; Time; Training; Transcript; Transcriptional Regulation; Translating; Translational Repression; Translations; Untranslated Regions; Update; Validation; Work; Yeasts; base; cell type; comparative; crosslink; improved; markov model; mouse genome; novel; tool; web-accessible

DESCRIPTION (provided by applicant): The function of any specific gene is dependent on both its product and the context in which the gene is expressed. Gene expression can be regulated during any process in the progression from genomic DMA to messenger RNA to translated protein. Post-transcriptional mechanisms (e.g., mRNA localization or degradation) provide control beyond that which can be achieved through purely transcriptional means, yet have been the subject of comparably less study than their transcriptional counterparts. Such regulation is often mediated by sequences located in the untranslated regions (UTR) of the transcript. Our objectives are the computational identification, characterization, and modeling of regulatory sequences that mediate post-transcriptional mRNA processing in eukaryotic organisms, focusing on the 3'-UTR. The results and tools generated throughout this project will be shared through publicly accessible web server interfaces, including extensive, bi-directional cross-linking with existing community databases. We have active and proposed additional collaborations with wet bench experimental scientists who work with model organisms, studying systems and biological processes that feature post-transcriptional regulatory control. Our efforts will initially focus on studies of early development (oogenesis, spermatogenesis, and embryogenesis), which feature periods of transcriptional silence (making post- transcriptional regulation a necessity), as well as extensive use of cell type and developmental stage specific transcript processing. We will work closely with our collaborators to generate testable hypotheses for phenomena such as differential selection of alternative 3'-processing sites and putative c/s-acting functional elements that mediate transcript localization, degradation, or translation. Their experimental results will be used to update our computational analysis, resulting in a collaborative, iterative process of modeling, hypothesis generation, and validation that will produce a better understanding of the functional aspects of 3'-UTR sequences. The principal relevance of the proposed work to public health lies in improved models of post- transcriptional gene regulation. Disease or developmental problems can arise from mutations that have no effect on the form of the final protein, but instead change the timing, location, or amount of protein generated. Our work will generate resources that facilitate the connection between regulatory activity and health implications.

描述（由申请人提供）：任何特定基因的功能都取决于其产物和基因表达的背景。基因表达可以在从基因组 DMA 到信使 RNA 再到翻译蛋白的任何过程中受到调节。转录后机制（例如 mRNA 定位或降解）提供的控制超出了通过纯转录手段所能实现的控制，但与转录后机制相比，其研究相对较少。这种调节通常由位于转录本非翻译区 (UTR) 的序列介导。我们的目标是对介导真核生物转录后 mRNA 加工的调控序列进行计算识别、表征和建模，重点关注 3'-UTR。整个项目产生的结果和工具将通过可公开访问的网络服务器接口共享，包括与现有社区数据库的广泛的双向交叉链接。我们积极并提议与湿台实验科学家进行更多合作，他们研究模型生物，研究以转录后调控为特征的系统和生物过程。我们的工作最初将集中于早期发育（卵子发生、精子发生和胚胎发生）的研究，其特点是转录沉默期（使转录后调控成为必要），以及细胞类型和发育阶段特定转录处理的广泛使用。我们将与我们的合作者密切合作，为诸如替代3'加工位点的差异选择和介导转录本定位、降解或翻译的推定的顺式/顺式作用功能元件等现象生成可检验的假设。他们的实验结果将用于更新我们的计算分析，从而产生建模、假设生成和验证的协作迭代过程，从而更好地理解 3'-UTR 序列的功能方面。拟议工作与公共卫生的主要相关性在于改进转录后基因调控模型。疾病或发育问题可能是由突变引起的，这些突变对最终蛋白质的形式没有影响，但会改变蛋白质生成的时间、位置或数量。我们的工作将产生资源，促进监管活动与健康影响之间的联系。