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

• 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
• 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' 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

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中广泛的远端3'UTR利用的机制和生物学信使RNA（mRNA）的3'非翻译区（3'UTR）是介导转录后基因调控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microRNA（miRNA）的短RNA对基因功能产生深远的积极或消极调控影响。近年来，人们认识到交替性多聚腺苷酸化（阿帕）可以根据细胞状态、组织特性或环境条件诱导3'UTR变异，为基因治疗提供了一种策略 协调数百个基因的转录后调控。然而，阿帕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阿帕的后果。 我们最近描述了果蝇中广泛的组织特异性阿帕趋势，包括中枢神经系统中大量的3'UTR延长。这包括数百个未注释的延伸，其长度范围对于通过北方分析检测的稳定转录物的实验验证的3 'UTR来说是前所未有的。我们正在进行的未发表的努力表明，这些原则在哺乳动物大脑中广泛保守。总之，这些出乎意料的宽而长的3'UTR延伸的存在对神经系统中的基因调控具有强烈的意义。特别是，我们假设，他们介导的独特的转录后神经元的需求，其不寻常的细胞结构强加的关键方面。 我们广泛的初步数据是不同的实验策略，我们建议阐明的基因组宽度，生物学效用，并在果蝇和哺乳动物系统的神经3'UTR延长的机制基础的基础。这项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。神经元阿帕网络的功能障碍可诱导神经系统疾病，而3'UTR延长机制的异位激活应严重扭曲脑外的基因调控网络。我们多方面的研究计划应该阐明这些过程。