Functional and Evolutionary Genomics of Ancient Small RNAs

描述(申请人提供)：在DNA(基因)的线性片段中编码的信息是地球上所有生命的基础。基因并不总是处于“开启”状态--相反，单个基因的活动是微调的，以应对各种内部和外部刺激。基因表达的调控对于人类和所有其他生物的几乎每一个生物过程都是至关重要的。最近发现，被称为microRNAs的小调控RNAs是动植物基因表达调控的主要组成部分。通过microRNAs调控特定的“靶”基因对于胚胎发育、器官发生和应激反应是至关重要的。一组核心的植物microRNA在非常不同的植物物种中调节同源靶标；这些古老的microRNA与靶标的相互作用被认为调节发育过程。同样的microRNA-靶相互作用如何指导高度分化的植物截然不同的发育模式和形态？它们最终是否控制着古老的、保守的基因表达套件，或者它们在不同的谱系中得到了不同的利用？该项目试图通过使用分子遗传学来阐明古代miRNAs在两种截然不同的陆地植物中的功能和调控网络，以回答这些问题。具体地说，本项目将1)从遗传上剖析光叶苔藓中microRNA机制的功能，2)分析两个截然不同的模式植物--光叶苔藓和开花植物拟南芥中同源的、古老的microRNA与目标相互作用的功能，以及3)经验地确定并比较这两个物种中由古老的microRNA-目标相互作用控制的基因调控网络。该项目还将实施一种研究microRNA功能的新方法，有可能在基础和应用研究中广泛应用。这项工作将揭示关键基因调控网络进化的详细分子图景。重要的是，microRNA功能的核心机制在植物、动物和人类之间是保守的。事实上，从过去对易于研究的植物中的microRNAs和其他小RNAs的研究中获得的基本知识直接促进了人类健康研究的进步，包括使用RNA干扰快速检测人类细胞中的基因功能，越来越多地认识到microRNAs在各种常见疾病中所起的作用，以及开发基于小RNA的治疗特定疾病的方法。通过利用植物系统中独特可用的强大分子遗传学工具，在对microRNA控制的基因调控网络的基本理解方面取得的进一步进展，肯定会继续为各种生物医学研究提供信息。公共卫生相关性：项目简介最近发现许多基因受microRNAs控制，包括几个与癌症和其他疾病有关的基因，但microRNA功能的分子细节在很大程度上仍不清楚。在人类、动物和植物中，microRNA功能的基本方面看起来是相同的，这使得对容易操纵的生物体的分析可以为人类过程提供信息。该项目将通过确定古老的microRNAs在易于研究的模式生物中的作用来揭示microRNA介导的基因控制的基本机制。

DESCRIPTION (provided by applicant): Information encoded within linear segments of DNA (genes) is the basis for all life on planet Earth. Genes are not "on" all of the time - on the contrary, the activities of individual genes are finely tuned in response to various internal and external stimuli. Regulation of gene expression is critical for almost every biological process in humans and all other organisms. Small regulatory RNAs termed microRNAs have recently been discovered to be major components of gene expression control in both animals and plants. The regulation of specific "target" genes by microRNAs is critical for embryonic development, organogenesis, and stress responses. A core set of plant microRNAs regulate homologous targets in very different plant species; these ancient microRNA-target interactions are thought to regulate developmental processes. How do the same microRNA-target interactions guide the very different developmental patterns and morphologies of highly divergent plants? Do they ultimately control ancient, conserved suites of gene expression, or have they been differentially utilized in different lineages? This project seeks to answer these questions by using molecular genetics to elucidate the functions and regulatory networks of ancient miRNAs in two very different land plants. Specifically, this project will 1) genetically dissect the functions of the microRNA machinery in the moss P. patens, 2) analyze the functions of homologous, ancient microRNA-target interactions in two very different model plant species, P. patens and the flowering plant Arabidopsis thaliana, and 3) empirically determine and compare the gene regulatory networks controlled by ancient microRNA-target interactions in these two species. This project also will implement a novel methodology for the study of microRNA functions with the potential for broad applicability in basic and applied research. A detailed molecular picture of the evolution of critical gene regulatory networks will emerge from this work. Importantly, the core mechanisms of microRNA function are conserved between plants, animals, and humans. Indeed, the basic knowledge gained from past research on microRNAs and other small RNAs in easily studied plants has directly contributed to advances in human health research, including the use of RNA-interference to rapidly assay gene function in human cells, the growing appreciation of the roles microRNAs play in various common diseases, and the development of small RNA-based therapies for specific ailments. Further advances in the basic understanding of microRNA-controlled gene regulatory networks, derived by exploiting the powerful molecular genetic tools uniquely available in plant systems, will certainly continue to inform a wide variety of biomedical research. PUBLIC HEALTH RELEVANCE: Project Narrative Many genes have recently been shown to be controlled by microRNAs, including several implicated in cancer and other diseases, but the molecular details of microRNA functions are still largely unknown. Fundamental aspects of microRNA function appear identical in humans, animals, and plants, which allows analyses in easily manipulated organisms to inform human processes. This project will reveal basic mechanisms of microRNA-mediated gene control by defining the roles of ancient microRNAs in readily studied model organisms.