Integrated Studies of 3'-UTR Mediated Gene Regulation

描述（由申请人提供）：任何特定基因的功能取决于其产物和基因表达的环境。基因表达可以在从基因组DNA到信使RNA再到翻译蛋白的任何过程中进行调节。转录后机制（例如，mRNA定位或降解）提供了超越通过纯转录手段可以实现的控制，但与其转录对应物相比，它们已经成为较少研究的主题。这种调节通常由位于转录物的非翻译区（UTR）中的序列介导。我们的目标是在真核生物中介导转录后mRNA加工的调控序列的计算鉴定、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。我们与湿台实验科学家积极并提出了额外的合作，他们与模式生物一起工作，研究具有转录后调控功能的系统和生物过程。我们的努力将首先集中在早期发育（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），以及广泛使用细胞类型和发育阶段特异性转录加工。我们将与我们的合作者密切合作，以产生可检验的假设的现象，如差异选择替代3 '-加工位点和假定的顺式/反式作用功能元件，介导转录定位，降解，或翻译。他们的实验结果将用于更新我们的计算分析，从而产生一个协作的、迭代的建模、假设生成和验证过程，这将更好地理解3'-UTR序列的功能方面。拟议的工作与公共卫生的主要相关性在于改进转录后基因调控的模型。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，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，促进监管活动和健康影响之间的联系。

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.