Mechanism and regulation of Hu family RNA binding proteins during neural alternative polyadenylation

Hu家族RNA结合蛋白在神经选择性多聚腺苷酸化过程中的机制和调控

• 批准号: 10328897
• 负责人: Eric C Lai
• 金额: $ 59.16万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328897
• 关键词: 3' Untranslated Regions; Affect; Automobile Driving; Binding Sites; Biochemistry; Bioinformatics; Biological; Biological Assay; Biology; Brain; Cells; Complex; Data; Defect; Development; Disease; Drosophila genus; ELAV protein; Embryo; Engineering; Exhibits; Family; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; HU Protein; Human; Individual; Light; Malignant Neoplasms; Mammals; Mediating; MicroRNAs; Molecular; Molecular Biology; Molecular Genetics; Mus; Mutant Strains Mice; Nervous system structure; Neurons; Neurophysiology - biologic function; Orthologous Gene; Outcome; Pathway interactions; Pattern; Phenotype; Physiology; Play; Polyadenylation; Post-Transcriptional Regulation; Pre-mRNA Polyadenylation Factor; Process; Protein Family; Protein Isoforms; RNA-Binding Proteins; Recording of previous events; Regulation; Reporter; Repression; Role; Site; System; Testing; Time; Tissues; Trans-Activators; Transcript; Transgenic Organisms; Translations; Vertebrates; Work; cohort; crosslinking and immunoprecipitation sequencing; derepression; disorder subtype; fly; genome-wide; genomic data; human disease; human embryonic stem cell; in vivo; interdisciplinary approach; interest; mRNA Stability; member; morphogens; mouse genetics; mouse model; mutant; nervous system disorder; neurodevelopment; neuromechanism; novel; programs; relating to nervous system; tool; transcriptome; transcriptome sequencing; trend; unpublished works

PROJECT ABSTRACT 3' untranslated regions (3' UTRs) are the hubs of post-transcriptional regulation, and contain the majority of binding sites for regulatory factors such as miRNAs and RNA binding proteins (RBPs). Moreover, it has recently become appreciated that most genes do not express a single 3' UTR, but instead express multiple 3' UTR isoforms through a process known as alternative polyadenylation (APA). Since APA can be deployed to coordinately shift the 3' UTR profiles of large cohorts of genes according to tissue identity, environmental condition, or disease status, APA can broadly affect the post- transcriptional landscape and profoundly impact gene expression programs. Nevertheless, very little remains known about the underlying mechanisms of how global APA programs are enacted. In ongoing work, we identify conserved, redundant roles for Hu family neural RBPs in driving a broad program of neural 3' UTR lengthening in both Drosophila and mammalian nervous system. Here, we will use molecular genetic assays and genomewide analyses to elucidate the mechanism for neural Hu proteins in conferring neural 3' UTR extensions. Since neural Hu factors have such powerful capacity to remodel the transcriptome, it may follow that they are under strict control. Indeed, we have also found that neural Hu genes in both Drosophila and mammals are subject to unexpectedly complex and strong post-transcriptional suppression outside of the nervous system. We have developed new genetic models to study these regulatory mechanisms and their phenotypic impacts, which may reveal new roles for these factors in developmental patterning and also have tangible implications for a class of human disease that is caused by misexpression of neural Hu proteins outside of the brain. Overall, this work will reveal new perspectives on the deployment of the distinctive neural post-transcriptional landscape and its in vivo biological importance.

项目摘要 3‘非翻译区(3’UTRs)是转录后调控的中枢， 并包含大多数调控因子的结合位点，如miRNAs和RNA 结合蛋白(RBPs)。此外，最近人们认识到，大多数基因 不表达单一的3‘非编码区，而是通过 这一过程被称为交替多聚腺苷(APA)。由于APA可以部署到 根据组织协调移动大的基因队列的3‘UTR谱 身份、环境条件或疾病状况，APA可广泛影响后- 转录景观和深刻影响基因表达程序。 然而，人们对全球经济一体化的潜在机制知之甚少 颁布了《行政程序法》计划。在正在进行的工作中，我们确定了以下方面的保守、冗余角色 胡氏家族神经RBPs在推动两边神经3‘非编码区延长广泛计划中的作用 果蝇和哺乳动物的神经系统。在这里，我们将使用分子遗传分析 以及全基因组分析，以阐明神经HU蛋白在 授予神经3‘非编码区延伸。因为神经HU因子有如此强大的 如果有能力重塑转录组，那么它们可能受到严格的控制。 事实上，我们还发现果蝇和哺乳动物的神经Hu基因都是 在外部受到出人意料的复杂和强烈的转录后抑制 神经系统。我们已经开发了新的遗传模型来研究这些调控 机制及其表型影响，这可能揭示这些因素的新作用 在发育模式上，也对人类的一类有着切实的影响 由大脑外的神经HU蛋白的错误表达引起的疾病。 总体而言，这项工作将揭示出部署特色鲜明的 神经转录后景观及其在体内的生物学意义。