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

摘要 细胞通过调节翻译和衰变来响应环境变化和压力 胞浆中的mRNAs。这种转录后调控对于维持适当的 细胞生理学。通常，这些调节程序保护细胞免受病理性压力。在……里面 然而，其他情况下，适应不良反应是疾病表型的基础。理解 这些动态的、响应环境的转录后调控计划至关重要 了解细胞生理学并承诺提供新的治疗靶点以支持保护 反应和压制破坏性的反应。 最近的工作已经编目了数百种信使核糖核酸结合蛋白。我们对如何 这些蛋白质影响它们结合的mRNAs已经落后于列举这些的研究 蛋白质，我们通常缺乏对它们在细胞中更广泛的作用的了解。我们的激励 假设这些蛋白质中的许多以特定的fic转录本为靶标并调节它们的翻译。 和稳定性，以协调的方式响应环境和细胞内的提示。 事实上，我们知道调节蛋白质结合编码功能相关基因的转录本。 并在促进腐朽或促进翻译之间切换以响应监管 磷酸化。我们认为，这代表了一种更广泛的模式。 这一提议的广泛的科学目标是阐明后-fi-C的功能网络。 细胞内的转录调控。我们将应用高吞吐量和公正的方法来 从信使核糖核酸结合蛋白向外工作，以便识别控制其 活动，调节其影响的上下游因素，以及监管 他们控制的程序。我们的工作将揭示如何以及为什么这样做的一般原则 基因的表达在转录后受到控制。我们还将开发能够 在广泛的其他生物系统中解决这一问题。

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.