From the start, the goal of this program has been the development and application of genome-wide approaches to systematic and quantitative analysis of gene expression patterns in cancer. In the eight years since we began this project, the experimental and analytical tools for systematic studies of global gene expression patterns at the level of transcript abundance have developed dramatically and they have become widely available and widely used for the study of cancer. The resulting studies have produced a wealth of new insight into cancer and they are even beginning to influence patient care. Profiling mRNA transcript levels, however, provides only a partial picture of the global gene expression program. While there is abundant evidence that regulation of the translation, subcellular localization and decay of mRNA are critical elements of biological regulation, practical and robust genome-wide approaches to studying these levels of regulation remain to be developed. As a result, our knowledge of the systems architecture, molecular mechanisms and biological roles of these regulatory mechanisms, including the roles they play in human cancer, is barely in its infancy. We therefore propose to develop practical, robust, high-throughput methods using DNA microarrays to profile three critical aspects of global regulation at the post-transcriptional level: translational regulation, regulation of mRNA degradation, and the specific interactions of RNA binding proteins with their targets. These studies will build on preliminary studies we've already begun in the Saccharomyces cerevisiae model system, but will focus on human cells. As the essential methodologies are developed, we will apply them to developing a foundational framework of knowledge, investigating the patterns in which these regulatory mechanisms are used in basic physiological and developmental programs, how they vary from one cell type to another and between individuals, and beginning to investigate the underlying molecular mechanisms. The goal is to develop both the experimental methodology and an interpretive framework to the point that these post-transcriptional levels of gene expression can be systematically profiled and studied on a genome-wide scale almost as routinely as transcript levels are today. ? ? ?
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