Regulation of mRNA translation by cis-acting sequences and trans-acting factors

虽然基因表达的调节被公认为对人类很重要 疾病，在理解转录后转录后的作用方面存在着根本的差距 流程。因为转录后过程对于调节 蛋白质生产，解决这一知识差距将促进更好的模型 基因型与表型的关系。与转录一样，信使核糖核酸的翻译是 受顺式作用序列和反式作用因子调控。上游开放阅读 框架(UORF)是大多数人类基因中发现的顺式作用调节元件，并且 一些与疾病相关的突变似乎会改变uORF的存在。初级阶段 我的实验室的重点是确定顺式作用序列和反式作用因子如何 控制平移。我们下一个资助期的目标是确定 人uORFs及其反式作用RNA结合蛋白的调节作用 (限制性商业惯例)。为了做到这一点，我们改编了我们的酵母大规模平行报道 用于人体组织培养的分析(MPRAs)。另外，我们的计算分析 已经确定了数千种灵长类保守的人类uORF，其中许多都有 在其起始密码子下游保守的RBP结合位点。绝大多数人 这些uORF还没有被功能研究。我们的创新方法结合了 精致的系统生物学工具与前沿的计算建模研究 这些无处不在的顺式调控元件的功能。拟议的研究是 意义重大，因为它有望从根本上促进我们对人类的理解 基因调控。

While the regulation of gene expression is well recognized as being important to human disease, there is a fundamental gap in understanding the role of post-transcriptional processes. Because post-transcriptional processes are critical for the regulation of protein production, addressing this knowledge gap will facilitate better models of the relationship between genotype and phenotype. Like transcription, mRNA translation is regulated by cis-acting sequences and trans-acting factors. upstream Open Reading Frames (uORFs) are cis-acting regulatory element found in most human genes, and some disease-linked mutations appear to alter the presence of uORFs. The primary focus of my laboratory is to determine how cis-acting sequences and trans-acting factors control translation. Our goal for the next funding period is to determine the functions of human uORFs and evaluate their regulation by trans-acting RNA binding proteins (RBPs). To accomplish this, we have adapted our yeast Massively Parallel Reporter Assays (MPRAs) for use in human tissue culture. In addition, our computational analysis has identified thousands of primate-conserved human uORFs, many of which have conserved RBP binding sites downstream of their start codons. The vast majority of these uORFs have not been functionally studied. Our innovative approach combines exquisite systems biology tools with cutting-edge computational modeling to investigate the functions of these ubiquitous cis-regulatory elements. The proposed research is significant because it is expected to fundamentally advance our understanding of human gene regulation.