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：
9241435
负责人：
Maria Barna
金额：
$ 50.51万
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/9241435
关键词：
5&apos Untranslated Regions Affect Attention 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 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 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（由适用提供）：对时空中基因表达的控制在使细胞“知道”它们在发育中的胚胎中的位置以及成为什么事物中起着重要作用，通常称为细胞规范。数十年的研究表明，在转录和转录后级别的基因表达控制中，许多调节层是协调这一过程的。相反，基因表达的翻译围节受到了较少的实验关注。最值得注意的是，主要的教条是，在蛋白质产生的水平上，核糖体 - 尽管具有非常复杂的分子机器 - 在翻译mRNA时具有构成性而非调节功能。我们的发现出乎意料地表明，胚胎发育和组织模式的基本方面由核糖体的高度调节功能控制。重要的是，我们已经表明，具有独特的蛋白质组成或活性会议的“专业核糖体”非常特异性，即如何将哺乳动物基因组解码为蛋白质。我们最近的研究也开始阐明mRNA模板中的表达信息如何通过核糖体赋予基因调节潜力来指导胚胎发育。特别是，我们的研究已经确定了嵌入了关键发育调节剂5'UTR的新型RNA调节剂，例如Homeobox（HOX）基因的整个子集，这些基因将基因产物在时间和空间中如何转化以对哺乳动物的身体计划进行模型。这些发现改变了我们对基因调节的理解，并将新的理解门户开放为嵌入脊椎动物5'UTRS中的附加调节层，这对于控制细胞规范，组织模式和胚胎发育至关重要。在此提案中，我们将采用一种高度多学科的方法来表征这种新颖的监管代码，以转化关键发育记录的转换，以进行转录后调节。在AIM1中，我们将表征一个在时间和空间中控制HOX基因表达所需的新型转录后电路。特别是，我们将采用一种多方面的遗传学方法，以揭示新型5'UTR RNA调节子的功能作用，包括IRES样和绑带元件在多个HOX基因5'Utrs中朝着其体内表达的关键方面和椎骨胚胎的构图的关键方面。在AIM2中，我们将表征TIE元素，TIE元素是一种新鉴定的RNA调节元件，具有极大的潜力，可以在功能上专门提高哺乳动物基因组的翻译。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剂的翻译控制的影响。这些研究将共同开放有关嵌入脊椎动物5'UTRS中的独特RNA元素制备的“语法规则”的新门户，该元素旨在扩大指导有机发育的发展基因表达程序。