Functional genomics of the dynamic molecular network controlling mRNA translation and decay

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ABSTRACT Cells respond to environmental changes and stresses by modulating the translation and decay of mRNAs in the cytosol. This post-transcriptional regulation is critical for maintaining proper cellular physiology. Often, these regulatory programs protect cells from pathological stresses. In other cases, however, maladaptive responses underlie disease phenotypes. Understanding these dynamic, environmentally responsive post-transcriptional regulatory programs is critical for understanding cell physiology and promises novel therapeutic targets to support protective responses and suppress damaging ones. Recent work has catalogued hundreds of mRNA-binding proteins. Our understanding of how these proteins affect the mRNAs they bind has lagged behind studies that enumerate these proteins, and we generally lack an understanding of their broader role in the cell. Our motivating hypothesis is that many of these proteins target specific transcripts and regulate their translation and stability in a coordinated fashion in response to environmental and intracellular cues. Indeed, we know of regulatory proteins that bind transcripts encoding functionally related genes and switch between promoting decay or promoting translation in response to regulatory phosphorylation. We believe that this represents a more widespread model. The broad scientific goal of this proposal is to elucidate the functional networks of post- transcriptional regulation in the cell. We will apply high-throughput and unbiased approaches to work outward from mRNA-binding proteins in order to identify the signals that control their activity, the upstream and downstream factors that mediate their effect, and the regulatory programs that they control. Our work will reveal the general principles governing how and why gene expression is controlled post-transcriptionally. We will also develop approaches that can be transferred to address this question in a wide array of other biological systems.