Functional and Evolutionary Genomics of Ancient Small RNAs

描述（由申请人提供）：在DNA（基因）线性片段中编码的信息是地球上所有生命的基础。基因并不是一直“开着”的——相反，单个基因的活动会对各种内部和外部刺激做出精细的调整。基因表达的调控对人类和所有其他生物的几乎所有生物过程都至关重要。被称为microrna的小调控rna最近被发现是动物和植物基因表达控制的主要组成部分。microrna对特定“靶”基因的调控对胚胎发育、器官发生和应激反应至关重要。一组核心的植物microrna在不同的植物物种中调控同源靶点；这些古老的microrna -靶标相互作用被认为调节着发育过程。相同的microrna -靶标相互作用如何指导高度分化植物的不同发育模式和形态？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被不同地利用？本项目试图通过使用分子遗传学来阐明两种非常不同的陆地植物中古代mirna的功能和调控网络来回答这些问题。具体来说，本项目将1)从遗传学上解剖苔藓中microRNA机制的功能，2)分析同源的古代microRNA-靶标相互作用在两个非常不同的模式植物物种——patens和开花植物拟南芥中的功能，以及3)经验确定和比较这两个物种中由古代microRNA-靶标相互作用控制的基因调控网络。该项目还将实现一种新的方法来研究microRNA的功能，在基础和应用研究中具有广泛的适用性。关键基因调控网络进化的详细分子图谱将从这项工作中浮现。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microrna和其他易于研究的植物小rna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干扰快速测定人类细胞中的基因功能，越来越多的人认识到microrna在各种常见疾病中的作用，以及针对特定疾病开发基于小rna的治疗方法。通过利用植物系统中独特的强大分子遗传工具，对microrna控制的基因调控网络的基本理解取得了进一步的进展，肯定会继续为各种生物医学研究提供信息。许多基因最近被证明是由microRNA控制的，包括一些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然未知。在人类、动物和植物中，microRNA功能的基本方面似乎是相同的，这使得对容易操纵的生物体的分析能够为人类的过程提供信息。该项目将通过定义古代microrna在模型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.