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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.