Mechanism and biology of widespread distal 3'UTR utilization in the CNS

CNS 中广泛使用远端 3UTR 的机制和生物学

基本信息

批准号：
8698063
负责人：
Eric C Lai
金额：
$ 48.09万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698063
关键词：
3&apos Untranslated Regions Algorithms Animal Model Animals Architecture Behavior Binding Sites Biochemical Biological Biological Models Biology Brain Calmodulin Cataloging Catalogs Cell Line Cells Computing Methodologies Data Data Set Databases Development Dissection Distal Drosophila genus Employee Strikes Engineering Equipment and supply inventories Exhibits Foundations Functional RNA Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic screening method Genome Genomics Homologous Gene Human Human Genome Individual Insecta Investments Knock-in Mouse Knowledge Length Location Malignant Neoplasms Mammals Mediating Messenger RNA Methods MicroRNAs Molecular Molecular Genetics Mus Nervous system structure Neuraxis Neurologic Neuronal Dysfunction Neurons Neurophysiology - biologic function Nucleic Acid Regulatory Sequences Open Reading Frames Pathway interactions Pattern Physiology Polyadenylation Post-Transcriptional Regulation Pre-mRNA Polyadenylation Factor Process Protein Isoforms Proteins RNA RNA Interference RNA Sequences RNA Stability RNA-Binding Proteins Reading Recruitment Activity Regulation Regulator Genes Research Signal Transduction System Tissues Transcript Transgenic Organisms Variant Work base crosslink fly forward genetics gene function genetic manipulation genome-wide human disease improved in vivo insight mouse genome mutant nervous system disorder neurodevelopment neuromechanism novel novel strategies programs public health relevance relating to nervous system screening success transcriptome sequencing trend

项目摘要

DESCRIPTION (provided by applicant): Mechanism and biology of widespread distal 3'UTR utilization in the CNS The 3' untranslated regions (3'UTRs) of messenger RNAs (mRNAs) are the predominant location of cis-regulatory sequences that mediate post-transcriptional gene regulation. 3'UTRs can impart profound positive or negative regulatory impact on gene function, via diverse RNA binding proteins (RBPs) and short RNAs termed microRNAs (miRNAs). In recent years, it has been appreciated that alternative polyadenylation (APA) can induce 3'UTR variation according to cell-state, tissue identity or environmental condition, providing a strategy for coordinate post-transcriptional regulation of hundreds of genes. However, the molecular mechanisms of APA are mostly unknown and only for a few genes have the consequences of disrupting APA been studied in intact animals. We recently described broad tissue-specific APA trends in Drosophila, including substantial 3'UTR lengthening in the central nervous system. This included hundreds of unannotated extensions, ranging into lengths unprecedented for experimentally- validated 3'UTRs of stable transcripts detected by Northern analysis. Our ongoing unpublished efforts reveal that these principles are broadly conserved in the mammalian brain. Altogether, the existence of these unexpectedly broad and long 3'UTR extensions has strong implications for gene regulation in the nervous system. In particular, we hypothesize that they mediate critical aspects of the unique post-transcriptional needs of neurons, imposed by their unusual cellular architecture. Our extensive preliminary data are the basis of diverse experimental strategies that we propose to elucidate the genomic breadth, the biological utility, and mechanistic underpinning to neural 3'UTR lengthening in Drosophila and mammalian systems. The proposed work exploits our established expertise with transcriptome analysis, miRNAs, post-transcriptional control, and neural development and function. We believe that the knowledge gained from our mechanistic and functional studies will have direct relevance for human disease. Dysfunction of the neuronal APA network may induce neurological conditions, while ectopic activation of the 3'UTR lengthening mechanism should severely distort gene regulatory networks outside of the brain. Our multi-faceted research program should illuminate these processes.

描述（由申请人提供）：CNS中广泛远端3'UTR利用的机制和生物学是Messenger RNA（mRNA）的3'未翻译区（3'UTRS）是介导转录后基因调节的顺式调控序列的主要位置。 3'UTR可以通过不同的RNA结合蛋白（RBP）和称为microRNAS（miRNA）的RNA结合蛋白（RBP）和短RNA对基因功能产生深远的正调节影响。近年来，人们认为，根据细胞态，组织身份或环境条件，替代聚腺苷酸化（APA）可以诱导3'UTR变化，从而提供策略用于坐标的数百个基因的转录后调节。然而，APA的分子机制大多未知，仅在少数基因中，就会在完整动物中研究破坏APA的后果。我们最近描述了果蝇中广泛的组织特异性APA趋势，包括中枢神经系统中的大量3'UTR延长。这包括数百个未注释的扩展，范围为实验验证的3'Utrs nortests northers northern Analysis检测到的稳定转录本的3'Utrs。我们正在进行的未发表的努力表明，这些原则在哺乳动物的大脑中是广泛保守的。总的来说，这些出乎意料的宽和长3'UTR扩展的存在对神经系统中的基因调节具有很大的影响。特别是，我们假设它们介导了神经元独特的转录后需求的关键方面，这些方面是由于其异常的细胞结构所施加的。我们广泛的初步数据是我们建议阐明基因组广度，生物实用程序和机械基础的不同实验策略的基础，该基因组宽度和机械基础是果蝇和哺乳动物系统中延长神经3'UTR的基础。拟议的工作利用了我们既定的专业知识，其中包括转录组分析，miRNA，转录后控制以及神经发育和功能。我们认为，从我们的机械和功能研究中获得的知识将与人类疾病具有直接相关性。神经元APA网络的功能障碍可能诱导神经系统疾病，而3'UTR延长机制的异位激活应严重扭曲大脑外的基因调节网络。我们的多方面研究计划应阐明这些过程。