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：
9208172
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/9208172
关键词：
3&apos Untranslated Regions Algorithms Animal Model Animals Architecture Behavior Binding Sites Biochemical Biological Biological Models Biology Brain Calmodulin Catalogs Cell Line Cells Computing Methodologies Data Data Set Development Dissection Distal Drosophila genome Drosophila genus Employee Strikes Engineering Equipment and supply inventories Exhibits Foundations Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic screening method Genome Genomics Human Human Genome Individual Insecta Investments Knock-in 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 Phenotype Physiology Polyadenylation Post-Transcriptional Regulation Pre-mRNA Polyadenylation Factor Process Protein Isoforms Proteins RNA RNA Interference RNA Sequences RNA Stability RNA-Binding Proteins Recruitment Activity Regulation Regulator Genes Research Signal Transduction System Tissues Transcript Transgenic Organisms Untranslated RNA Untranslated Regions 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 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 中广泛使用远端 3'UTR 的机制和生物学信使 RNA (mRNA) 的 3' 非翻译区 (3'UTR) 是介导转录后的顺式调控序列的主要位置基因调控。 3'UTR 可通过多种 RNA 结合蛋白 (RBP) 和称为 microRNA (miRNA) 的短 RNA 对基因功能产生深远的积极或消极调节影响。近年来，人们认识到选择性多腺苷酸化（APA）可以根据细胞状态、组织身份或环境条件诱导 3'UTR 变异，从而提供了一种策略用于协调数百个基因的转录后调控。然而，APA 的分子机制大多是未知的，并且只有少数基因在完整动物中研究了破坏 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 3'UTR 的显着延长。其中包括数百个未注释的延伸，其长度对于 Northern 分析检测到的经过实验验证的稳定转录本的 3'UTR 来说是前所未有的。我们正在进行的未发表的研究表明，这些原理在哺乳动物大脑中广泛保守。总而言之，这些出乎意料的宽且长的 3'UTR 延伸的存在对神经系统中的基因调控具有重要意义。特别是，我们假设它们介导神经元独特的转录后需求的关键方面，这是由其不寻常的细胞结构所强加的。我们广泛的初步数据是多种实验策略的基础，我们建议阐明果蝇和哺乳动物系统中神经 3'UTR 延长的基因组广度、生物学效用和机制基础。拟议的工作利用了我们在转录组分析、miRNA、转录后控制以及神经发育和功能方面已建立的专业知识。我们相信，从机制和功能研究中获得的知识将与人类疾病直接相关。神经元 APA 网络的功能障碍可能会诱发神经系统疾病，而 3'UTR 延长机制的异位激活会严重扭曲大脑外部的基因调控网络。我们的多方面研究计划应该阐明这些过程。