MicroRNA genes and their functions

描述（由申请人提供）：RNA分子在调节真核基因表达中可能发挥的作用已经转移到中心阶段。最近发现两种小的调节RNA lin-4 RNA和let-7 RNA在C.在线虫的发育过程中，它们是一类21- 24-nt的非编码RNA的成员，称为microRNA（miRNAs）。迄今为止，在C.线虫、果蝇和人类。该提案的重点是这类新发现的基因的基因组学和功能基因组学，其广泛的长期目标是了解RNA在调节基因表达中的作用。具体目标是：1）使用分子方法鉴定额外的miRNA基因，2）开发和应用用于鉴定miRNA基因的生物信息学工具，3）检查破坏miRNA基因或功能的后果。目标#1和#2的实验将鉴定和检查数百个miRNA基因的表达，包括线虫和鱼类中的大多数miRNA基因。他们还将检测小鼠和人类的候选基因。因此，他们将极大地扩展数据库中miRNA基因的注释，这是所有生物学家的资源，对那些关注真核基因调控，发育和疾病的人特别有价值。目标#1的实验还将在植物和真菌中寻找miRNA，以扩大这些非编码RNA的已知系统发育分布。目标#3的实验将尝试敲除C.优雅他们还将探索抑制斑马鱼中miRNA功能的方法。miRNA破坏的表型将提供关键的见解，哪些调控网络包括miRNA，以及哪些部分的miRNA在发育，分化和其他过程中具有可辨别的，非冗余的作用。由于对这类新发现的基因知之甚少，人们对它们在人类中可能发挥作用的过程进行了广泛的猜测。在模式生物中鉴定miRNA基因并调查其功能将为理解miRNA在人类中的作用和了解其功能障碍如何导致疾病提供重要的见解和试剂。

DESCRIPTION (provided by applicant): The role that RNA molecules might be playing in modulating eukaryotic gene expression has moved to center stage. It has recently been discovered that two small regulatory RNAs, lin-4 RNA and let-7 RNA, which control the timing of cell divisions during C. elegans development, are members of a large class of 21- to 24-nt noncoding RNAs, called microRNAs (miRNAs). Thus far, dozens of miRNA genes have been reported in C. elegans, Drosophila, and humans. This proposal focuses on the genomics and functional genomics of this newly identified class of genes, with the broad, long-term objective of understanding the roles of RNA in regulating gene expression. The specific aims are: 1) to use molecular methods to identify additional miRNA genes, 2) to develop and apply bioinformatic tools for identifying miRNA genes, and 3) to examine the consequence of disrupting miRNA genes or functions.Experiments of Aims #1 and #2 will identify and examine the expression of hundreds of miRNA genes, including most of the miRNA genes in nematodes and fish. They will also detect mouse and human candidate genes. Thus, they will greatly expand the annotation of miRNA genes in the databases-a resource for all biologists, and of particular value for those concerned with eukaryotic gene regulation, development, and disease. Experiments of Aim #1 will also search for miRNAs in plants and fungi, in an effort to expand the known phylogenetic distribution of these noncoding RNAs. Experiments of Aim #3 will attempt to knockout 100 miRNA genes in C. elegans. They will also explore methods for inhibiting miRNA function in zebrafish. The phenotypes of miRNA disruptions will provide key insights as to which regulatory networks include miRNAs and what fraction of miRNAs have discernable, non-redundant roles in development, differentiation and other processes. Because so little is known about this newly identified class of genes, speculation is rife on the processes in which they might function in humans. Identifying the miRNA genes and surveying their functions in model organisms will provide important insights and reagents for understanding the roles of miRNAs in humans and learning how their dysfunction might contribute to disease.