MicroRNA genes and their functions

MicroRNA基因及其功能项目摘要/摘要RNA分子在真核生物基因表达过程中所起的作用已经转移到中心舞台。陆生植物、哺乳动物和其他双侧动物都有大约100到400多个基因，这些基因产生大约22个核苷酸的非编码RNA，称为microRNA（miRNAs）。microRNA与蛋白质编码基因的mRNA配对，指导这些信息的转录后抑制。由于单个哺乳动物miRNA可以靶向数百个信息，因此miRNA对mRNA的抑制和进化具有广泛的影响。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）鉴定额外的miRNA基因，2）改进和扩展miRNA靶鉴定，和3）确定miRNA介导的抑制的分子后果。目标#1的实验将使用高通量测序来鉴定许多miRNA基因，包括先前未识别的人类基因，从而显著增加（和校正）该基因类别的注释。基因发现也将扩展到基础动物，包括海绵和刺胞藻，以阐明这种基因调控模式的进化起源。目标#2的实验将使用分子和比较基因组方法来提供一个更精确和全面的预测目标列表，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#3的实验将确定从减少的转录物积累中可以辨别miRNA介导的阻遏的程度。他们还可能识别出许多新的靶点，而不是目前在mRNA表达阵列上检测到的靶点，从而提供改进和扩展靶点预测所需的大型定量数据集。由于超过三分之一的人类基因一直处于选择性压力下，以维持它们与一组广泛保守的miRNA的配对，因此miRNA已经被证明在哺乳动物发育，病毒感染和癌症中发挥重要作用也就不足为奇了。了解miRNA基因、它们可能的靶点以及它们作用的分子后果将有助于确定miRNA的其他功能，并了解它们的功能障碍如何导致人类疾病。 公共卫生相关性： 该提案的实验重点是称为microRNA的RNA短片段，它可以与细胞的蛋白质合作，以确定单个基因产生多少蛋白质，包括许多与癌症和其他疾病有关的基因。目标是找到未被识别的microRNA，了解如何最好地预测microRNA调节哪些基因，并确定它们对蛋白质输出的影响程度。实现这些目标将揭示为什么microRNA是正常生长和发育所必需的，以及它们的功能障碍如何导致人类疾病。

DESCRIPTION (provided by applicant): MicroRNA Genes and Their Functions Project Summary/Abstract The role that RNA molecules play during eukaryotic gene expression has moved to center stage. Land plants, mammals, and other bilateral animals each have from ~100 to >400 genes that produce ~22-nt noncoding RNAs, called microRNAs (miRNAs). MicroRNAs pair to the mRNAs of protein-coding genes to direct the posttranscriptional repression of these messages. Because a single mammalian miRNA can target hundreds of messages, miRNAs have a widespread impact on mRNA repression and evolution. 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 identify additional miRNA genes, 2) to improve and expand miRNA target identification, and 3) to determine the molecular consequences of miRNA-mediated repression. Experiments of Aim #1 will use high-throughput sequencing to identify many miRNA genes, including previously unrecognized human genes, substantially increasing (and correcting) annotations of this gene class. Gene discovery will also be extended to basal animals, including sponge and cnideria, to shed light on the evolutionary origins of this mode of gene regulation. Experiments of Aim #2 will use molecular and comparative genomic approaches to provide a more precise and comprehensive list of predicted targets a resource for all biologists, and of particular value for those concerned with eukaryotic gene regulation, development, and disease. Experiments of Aim #3 will determine the extent to which miRNA-mediated repression can be discerned from reduced transcript accumulation. They also will likely identify many new targets beyond those currently detected on mRNA expression arrays and thereby provide large, quantitative datasets needed for improving and expanding target predictions. Because more than a third of the human genes have been under selective pressure to maintain their pairing to a set of broadly conserved miRNAs, it is no surprise that miRNAs have already been shown to play important roles in mammalian development, viral infection, and cancer. Knowing the miRNA genes, their likely targets, and the molecular consequences of their action will be useful for determining additional functions of miRNAs and learning how their dysfunction can contribute to human disease. Public Health Relevance: The experiments of this proposal focus on short snippets of RNA called microRNAs, which can collaborate with the proteins of the cell to determine how much protein is produced from individual genes, including many genes implicated in cancer and other diseases. The goals are to find microRNAs that had gone unrecognized, to learn how best to predict which genes the microRNAs regulate, and to determine the magnitude of their effects on protein output. Achieving these goals will shed light on why microRNAs are needed for normal growth and development, and how their dysfunction can contribute to human diseases.