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重要， 疾病，在理解转录后的作用方面存在根本性的差距。 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。像转录一样，mRNA翻译是 由顺式作用序列和反式作用因子调节。上游开路阅读 框架（uORF）是在大多数人类基因中发现的顺式作用调控元件， 某些疾病相关突变似乎改变了uORF的存在。主 我实验室的重点是确定顺式作用序列和反式作用因子 控制翻译。我们下一个资助期的目标是确定 人uORFs和评估其通过反式作用RNA结合蛋白的调节 （限制性商业惯例）。为了实现这一点，我们已经调整了我们的酵母大规模并行报告 用于人体组织培养的试验（MPRA）。此外，我们的计算分析 已经鉴定了数千个灵长类动物保守的人类uORF，其中许多具有 保守的RBP结合位点下游的起始密码子。绝大多数 这些uORF尚未进行功能研究。我们的创新方法结合了 精致的系统生物学工具与尖端的计算建模， 这些普遍存在的顺式调控元件的功能。拟议的研究是 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.