5'UTR RNA Regulons in ribosome-mediated control of embryonic development

核糖体介导的胚胎发育控制中的 5UTR RNA 调节子

基本信息

批准号：
9010546
负责人：
Maria Barna
金额：
$ 50.6万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9010546
关键词：
5&apos Untranslated Regions Accounting Affect Attention Beryllium Biology Cells Child Childhood Cleft Palate Code Complex Congenital Abnormality Development Developmental Cell Biology Developmental Gene Diamond-Blackfan anemia Disease Elements Embryo Embryonic Development Employee Strikes Enhancers Failure Gene Expression Gene Expression Regulation Generic Drugs Genetic Transcription Growth Hair Hereditary hypotrichosis simplex Homeobox Homeobox Genes Homeodomain Proteins Human Indium Internal Ribosome Entry Site Laboratories Limb structure Link Mediating Messenger RNA Molecular Molecular Machines Mutation Nature Organogenesis Pancytopenia Pattern Phenotype Play Positioning Attribute Post-Transcriptional Regulation Process Production Proteins RNA RNA-Binding Proteins Regulation Regulator Genes Regulatory Element Regulon Research Ribosomal Proteins Ribosomes Role Seminal Specificity Spleen Time Tissues Transcript Transgenic Organisms Translating Translational Repression Translations Untranslated Regions Variant base cell type embryo tissue frontier gene product genetic approach human disease in vivo innovation insight interdisciplinary approach mammalian genome novel programs public health relevance vertebrate embryos

项目摘要

DESCRIPTION (provided by applicant): Control of gene expression in space and time plays an important role in enabling cells to "know" where they are in the developing embryo and what to become, a process often referred to as cellular specification. Decades of research have demonstrated numerous layers of regulation in control of gene expression, at both the transcriptional and post-transcriptional level, which coordinate this process. Translational contro of gene expression has, on the contrary, received less experimental attention. Most notably, the prevailing dogma is that at the level of protein production, the ribosome -although an immensely complex molecular machine- possesses a constitutive rather than regulatory function in translating mRNAs. Our findings unexpectedly reveal that fundamental aspects of embryonic development and tissue patterning are instead controlled by a highly regulatory function of the ribosome. Importantly, we have shown that "specialized ribosomes" harboring a unique protein composition or activity confer tremendous specificity to how the mammalian genome is decoded into proteins. Our recent studies have also begun to elucidate how expression information encoded within the mRNA template confers gene regulatory potential by the ribosome to guide embryonic development. In particular, our research has identified novel RNA regulons embedded within the 5'UTRs of key developmental regulators, such as entire subsets of Homeobox (Hox) genes, which direct how gene products are translated in time and space to pattern the mammalian body plan. These findings transform our understanding of gene regulation and open a new portal of understanding into an additional layer of regulation embedded within vertebrate 5'UTRs vital to control of cell specification, tissue patterning, and embryonic development. In this proposal we will undertake a highly multidisciplinary approach to characterize this novel regulatory code for translational control of key developmental transcripts that primes them for post- transcriptional regulation. In Aim1 we will characterize a novel post-transcriptional circuitry required for control of Hox gene expression in time and space. In particular, we will undertake a multi-faceted genetic approach to uncover the functional roles of novel 5'UTR RNA Regulons including IRES-like and TIE elements in multiple Hox genes 5'UTRs towards key aspects of their expression in vivo and patterning of the vertebrate embryo. In Aim2 we will characterize the TIE element, a newly identified RNA regulatory element with remarkable potential to functionally specialize the translation of the mammalian genome. In Aim3 we will more broadly define the impact of RNA binding proteins on IRES-mediated translational control of key vertebrate developmental regulators. Together, these studies will open a new portal of understanding into the "grammatical rules" facilitated by unique RNA elements embedded within vertebrate 5'UTRs, which serves to expand developmental gene expression programs guiding organismal development.

描述（由申请人提供）：基因表达在空间和时间上的控制在使细胞“知道”它们在发育中的胚胎中的位置以及将变成什么方面发挥着重要作用，这一过程通常被称为细胞规范数十年的研究。相反，在转录和转录后水平上，基因表达的控制具有多层调控，而基因表达的翻译控制却受到较少的实验关注。在尽管核糖体是一种极其复杂的分子机器，但在蛋白质生产水平上，核糖体在翻译 mRNA 时具有组成性功能而非调节功能。我们的研究结果出人意料地揭示了胚胎发育和组织模式的基本方面是由核糖体的高度调节功能控制的。重要的是，我们已经证明，具有独特蛋白质组成或活性的“特殊核糖体”赋予哺乳动物基因组如何解码为蛋白质的巨大特异性。 mRNA 模板内编码的表达信息赋予核糖体指导胚胎发育的基因调控潜力。特别是，我们的研究发现了嵌入关键发育调节因子 5'UTR 中的新型 RNA 调节子，例如同源框 (Hox) 基因的整个子集。这些发现改变了我们对基因调控的理解，并为了解脊椎动物体内的额外调控层打开了新的大门。 5'UTR 对细胞规格、组织模式和胚胎发育的控制至关重要。在本提案中，我们将采用高度多学科的方法来表征这种新的调控代码，用于关键发育转录本的翻译控制，从而为转录后调控做好准备。我们将表征在时间和空间上控制 Hox 基因表达所需的新型转录后电路，特别是，我们将采用多方面的遗传方法来揭示新型 5'UTR RNA 调节子的功能作用，包括。多个 Hox 基因 5'UTR 中的 IRES 样元件和 TIE 元件在体内表达和脊椎动物胚胎模式的关键方面，我们将表征 TIE 元件，这是一种新发现的 RNA 调节元件，具有功能特化的巨大潜力。在 Aim3 中，我们将更广泛地定义 RNA 结合蛋白对 IRES 介导的关键脊椎动物发育调节因子的翻译控制的影响。脊椎动物 5'UTR 中嵌入的独特 RNA 元件促进了“语法规则”，它有助于扩展指导有机体发育的发育基因表达程序。