Regulatory roles of the epitranscriptome and RNA structurome during vertebrate development

表观转录组和RNA结构组在脊椎动物发育过程中的调控作用

• 批准号: 10797217
• 负责人: Jean-Denis Beaudoin
• 金额: $ 5.47万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797217
• 关键词: Affect; Animals; Automobile Driving; Defect; Development; Disease; Embryo; Failure; Fertilization; Functional disorder; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Human Development; Inherited; Investigation; Knowledge; Maps; Maternal Messenger RNA; Mediating; Messenger RNA; Modification; Molecular; Organism; Post-Transcriptional Regulation; Process; Proteins; RNA; RNA Folding; Regulation; Regulator Genes; Role; Shapes; Structure; Testing; Work; Zebrafish; cellular development; epitranscriptome; gene regulatory network; human disease; in vivo Model; innovation; interest; loss of function; mRNA Decay; multiple omics; novel strategies; posttranscriptional; programs; sperm cell; transcriptome; zygote

PROJECT SUMMARY/ABSTRACT (as submitted in original application) In all animals, the maternal-to-zygotic transition allows the transfer of information required for a single zygote to develop into a mature organism. After fertilization, the maternal program, composed of maternally-inherited mRNAs and proteins, drives cellular development and is replaced by the zygotic program. Because this transition occurs primarily in a transcriptionally silent embryo, it relies heavily on post-transcriptional regulation. Failure to properly regulate maternally-inherited mRNAs generally leads to developmental arrest or abnormalities. Recent studies have shown that maternal mRNAs are decorated with RNA modifications, collectively known as the ‘epitranscriptome’, that correlate with different mRNA fates. Moreover, we and others performed global analyses of mRNA structure dynamics during the maternal-to-zygotic transition and identified numerous regions that are structurally remodeled during this fundamental process, many of which impact mRNA decay. These studies suggest that RNA modifications and dynamic RNA structures are emerging as key regulators of gene expression during the maternal-to-zygotic transition. However, the detailed landscape of the epitranscriptome and dynamic RNA structures, and their roles in gene regulation during the maternal-to-zygotic transition remain poorly understood. Furthermore, RNA modifications and structures affect one another to regulate RNA functions, but little is known about how they interact to control gene expression during vertebrate development. The primary goal of my lab is to understand how the epitranscriptome and RNA structures mediate gene regulatory networks, separately and cooperatively, during vertebrate development and how their dysfunction promotes developmental defects or diseases. Here, we hypothesize that RNA modifications and structures interact with trans-factors to participate in the post-transcriptional regulatory landscape driving vertebrate development. To test this hypothesis, we will combine zebrafish —an in vivo model of vertebrate development— and its genetic toolbox with innovative multi-omics approaches. Over the next five years, we will inspect the native transcriptome to generate global, yet detailed, maps of the epitranscriptome during the maternal-to-zygotic transition, and study how specific RNA modifications impact gene expression. We will also decipher the RNA folds formed by dynamic regions of the transcriptome and analyze their effect on RNA regulation. We will identify trans-factors interacting with RNA modifications and structures of interest and study the consequences of their loss-of-function on gene expression and vertebrate development. Finally, we will examine how RNA modifications and structures cooperate to modulate post-transcriptional regulation. Successful completion of these investigations will greatly increase the existing knowledge of how RNA modifications and structures orchestrate post-transcriptional regulation, and will expand our understanding of the molecular mechanisms shaping vertebrate development.

项目概要/摘要（与原始申请中提交的内容相同） 在所有动物中，母体到合子的转变允许单个合子所需的信息转移到 发育成成熟的有机体。受精后，母体程序，由母体遗传的 mRNA和蛋白质驱动细胞发育，并被合子程序取代。因为这种转变 它主要发生在转录沉默的胚胎中，它严重依赖于转录后调节。未能 适当调节母体遗传的mRNA通常导致发育停滞或异常。最近 研究表明，母体mRNA被RNA修饰修饰，统称为 与不同mRNA命运相关的“表转录组”。此外，我们和其他人进行了全球分析， 在母体到合子过渡期间的mRNA结构动态，并确定了许多区域， 在这一基本过程中结构重塑，其中许多影响mRNA衰变。这些研究 表明RNA修饰和动态RNA结构正在成为基因表达的关键调节因子 在母体到合子的过渡期。然而，详细的景观的缩影和动态 RNA的结构，以及它们在母细胞向合子过渡过程中的基因调控作用仍然很差 明白此外，RNA修饰和结构相互影响以调节RNA功能， 在脊椎动物的发育过程中，它们是如何相互作用来控制基因表达的，目前还知之甚少。主 我实验室的目标是了解表转录组和RNA结构如何介导基因调控网络， 单独和合作，在脊椎动物的发展，以及他们的功能障碍如何促进发展 缺陷或疾病。在这里，我们假设RNA修饰和结构与反式因子相互作用， 参与驱动脊椎动物发育的转录后调控景观。为了验证这一 假设，我们将结合联合收割机斑马鱼-一种脊椎动物发育的体内模型-和它的遗传工具箱 创新的多组学方法。在接下来的五年里，我们将检查本地转录组， 在母体到合子的转变过程中产生全局但详细的表转录组图谱，并研究 特定的RNA修饰如何影响基因表达。我们还将破译由动力学形成的RNA折叠， 转录组的区域，并分析其对RNA调控的影响。我们将确定相互作用的反式因子 与RNA修饰和感兴趣的结构，并研究其功能丧失对基因的影响， 表达和脊椎动物发育。最后，我们将研究RNA修饰和结构 协同调节转录后调节。成功完成这些调查将大大 增加RNA修饰和结构如何协调转录后的现有知识 调控，并将扩大我们的理解的分子机制塑造脊椎动物的发展。