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. ? ? ?
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