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都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DMA到信使RNA到翻译蛋白的任何过程中受到调节。转录后机制（例如mRNA的定位或降解）提供了超越纯粹转录手段的控制，但与转录机制相比，研究的主题相对较少。这种调控通常是由位于转录物的非翻译区（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鉴定、表征和建模，重点是3'-UTR。整个项目产生的结果和工具将通过可公开访问的web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。我们与研究模式生物的湿台式实验科学家积极合作，研究以转录后调控控制为特征的系统和生物过程。我们的工作将首先集中在早期发育（卵子发生、精子发生和胚胎发生）的研究上，这些研究以转录沉默期为特征（使得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定位、降解或翻译的推定c/s作用功能元件等现象产生可测试的假设。他们的实验结果将用于更新我们的计算分析，从而形成一个协作、迭代的建模、假设生成和验证过程，从而更好地理解3'-UTR序列的功能方面。提出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。

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.