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

项目摘要 3'非翻译区（3'UTR）是转录后调控的枢纽， 并含有大部分调节因子如miRNA和RNA的结合位点 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' UTR，而是通过一个或多个3' UTR亚型表达多个3' UTR亚型。 这一过程称为交替多聚腺苷酸化（阿帕）。由于阿帕可以部署到 根据组织协调地改变大群基因的3' UTR谱， 身份，环境条件或疾病状态，阿帕可以广泛影响后， 转录景观和深刻影响基因表达程序。 尽管如此，我们对全球化的潜在机制知之甚少。 阿帕计划已经实施。在正在进行的工作中，我们确定了保守的，冗余的角色， Hu家族神经RBP在驱动两种细胞中神经3'UTR延长的广泛程序中的作用 果蝇与哺乳动物神经系统。在这里，我们将使用分子遗传分析 和全基因组分析，以阐明神经Hu蛋白在 赋予神经3 ′ UTR延伸。由于神经Hu因子具有如此强大的 由于它们有能力重塑转录组，因此可能受到严格控制。 事实上，我们还发现果蝇和哺乳动物的神经Hu基因都是 受到出乎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基因。 机制及其表型影响，这可能揭示这些因素的新作用 在发展模式中， 由脑外神经Hu蛋白的错误表达引起的疾病。 总的来说，这项工作将揭示新的视角部署的独特的 神经转录后景观及其在体内生物学的重要性。

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.