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

描述(申请人提供)：中枢神经系统中广泛利用3‘端非编码区的机制和生物学信使RNA(MRNAs)的3’非翻译区(3‘UTRs)是调节转录后基因调控的顺式调控序列的主要位置。3‘UTRs可以通过不同的RNA结合蛋白(RBPs)和称为microRNAs(MiRNAs)的短RNAs对基因功能产生深远的积极或消极的调控影响。近年来，人们认识到交替多聚腺苷酸化(APA)可以根据细胞状态、组织特性或环境条件诱导3‘UTR变异，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，只有少数基因在完整的动物身上研究了破坏APA的后果。我们最近描述了果蝇广泛的组织特异性APA趋势，包括中枢神经系统中显著的3‘非编码区延长。这包括数百个未注释的延伸，其长度在Northern分析检测到的经实验验证的稳定转录本的3‘UTRs中是前所未有的。我们正在进行的未发表的努力表明，这些原理在哺乳动物的大脑中广泛保守。总之，这些出人意料的广泛和长的3‘非编码区延伸的存在对神经系统中的基因调控有很大的影响。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，这些需求是由其不寻常的细胞结构强加的。我们广泛的初步数据是我们提出的各种实验策略的基础，这些策略旨在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。这项拟议的工作利用了我们在转录组分析、miRNAs、转录后控制以及神经发育和功能方面的现有专业知识。我们相信，从我们的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导致神经系统疾病，而3‘UTR延长机制的异常激活将严重扭曲脑外的基因调控网络。我们的多方面研究计划应该能阐明这些过程。

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 Our ongoing unpublished efforts reveal that these principles are broadly conserved in the mammalian brain.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.