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: 7141986
• 负责人: JOEL H GRABER
• 金额: $ 25.2万
• 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/7141986
• 关键词: bioinformatics; chemical models; chemical structure function; computational biology; developmental genetics; embryogenesis; gene expression; genetic regulation; model design /development; molecular biology information system; nucleic acid sequence; oogenesis; posttranscriptional RNA processing; spermatogenesis; statistics /biometry

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 DNA 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(申请人提供)：任何特定基因的功能都取决于其产物和表达该基因的环境。基因表达在从基因组DNA到信使RNA再到翻译蛋白的任何过程中都可以被调控。转录后机制(例如，信使核糖核酸的定位或降解)提供了超出纯转录方式所能实现的控制，但与转录机制相比，研究相对较少。这种调控通常是由位于转录本的非翻译区(UTR)的序列介导的。我们的目标是对真核生物中介导转录后mRNA加工的调控序列进行计算识别、表征和建模，重点是3‘-UTR。整个项目产生的成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双向交叉链接。我们已经积极并提议与湿凳实验科学家进行更多的合作，他们与模式生物合作，研究以转录后调控为特征的系统和生物过程。我们的努力最初将集中在早期发育(卵子发生、精子发生和胚胎发生)的研究上，这些研究以转录沉默时期为特征(使转录后调控成为必要)，以及广泛使用细胞类型和发育阶段特定的转录处理。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本地化、降解或翻译的假定的c/S作用功能元件等现象产生可检验的假说。他们的实验结果将用于更新我们的计算分析，导致建模、假设生成和验证的协作、迭代过程，这将产生对3‘-UTR序列功能方面的更好理解。这项拟议工作与公共健康的主要相关性在于改进了转录后基因调控的模型。疾病或发育问题可能源于突变，这些突变对最终蛋白质的形式没有影响，而是改变了产生蛋白质的时间、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。