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: 10543867
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543867
• 关键词: 3' Untranslated Regions; Affect; Amaze; Automobile Driving; Binding Sites; Biochemistry; Bioinformatics; Biological; Biological Assay; Biology; Brain; Cells; Complex; Data; Defect; Development; Disease; Drosophila genus; Embryo; Engineering; Exhibits; Family; Gene Expression; Genes; Genetic; Genetic Models; Genomics; HU Protein; Human; Individual; Malignant Neoplasms; Mammals; Mediating; MicroRNAs; Molecular; Molecular Biology; Molecular Genetics; Mus; Mutant Strains Mice; Nervous System; Neurons; Neurophysiology - biologic function; Orthologous Gene; Outcome; Pathway interactions; Pattern; Phenotype; Physiology; Play; Poly A; Polyadenylation; Post-Transcriptional Regulation; Pre-mRNA Polyadenylation Factor; Process; Protein Family; Protein Isoforms; RNA-Binding Proteins; Recording of previous events; Regulation; Reporter; Reporter Genes; 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; neural; neurodevelopment; neuromechanism; novel; posttranscriptional; programs; tool; transcriptome; transcriptome sequencing; trend; unpublished works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'UTR）是转录后调控的中心， 并包含 miRNA 和 RNA 等调节因子的大部分结合位点 结合蛋白（RBP）。此外，最近人们认识到大多数基因 不表达单个 3' UTR，而是通过 过程称为替代聚腺苷酸化 (APA)。由于 APA 可以部署到 根据组织协调转移大量基因的 3' UTR 图谱 身份、环境条件或疾病状况，APA 可以广泛影响术后 转录景观并深刻影响基因表达程序。 然而，人们对于全球性影响的根本机制知之甚少。 制定 APA 计划。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 在驱动神经 3' UTR 延长的广泛程序中 果蝇和哺乳动物神经系统。在这里，我们将使用分子遗传学检测 和全基因组分析以阐明神经 Hu 蛋白的机制 赋予神经 3' UTR 延伸。既然神经胡因素有如此强大的作用 重塑转录组的能力，因此它们可能受到严格控制。 事实上，我们还发现果蝇和哺乳动物的神经 Hu 基因 受到意想不到的复杂和强烈的转录后抑制 神经系统。我们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 的发展模式，并且对一类人类也有切实的影响 由大脑外神经 Hu 蛋白的错误表达引起的疾病。 总体而言，这项工作将揭示部署独特的新视角。 神经转录后景观及其体内生物学重要性。

项目成果

A Genome-Wide Survey of Sexually Dimorphic Expression of Drosophila miRNAs Identifies the Steroid Hormone-Induced miRNA let-7 as a Regulator of Sexual Identity.

果蝇 miRNA 性别二态性表达的全基因组调查确定类固醇激素诱导的 miRNA let-7 是性别认同的调节因子。

• 发表时间: 2014-07-29
• 作者: Fagegaltier, Delphine;König, Annekatrin;Gordon, Assaf;Lai, Eric C;Gingeras, Thomas R;Hannon, Gregory J;Shcherbata, Halyna R
• 通讯作者: Shcherbata, Halyna R

Alternative polyadenylation in the nervous system: to what lengths will 3' UTR extensions take us?

神经系统中的替代多聚腺苷酸化：3 UTR 延伸将带我们达到什么长度？

• 发表时间: 2014-08
• 作者: Miura, Pedro;Sanfilippo, Piero;Shenker, Sol;Lai, Eric C
• 通讯作者: Lai, Eric C

Transcriptional Regulation of the Glutamate/GABA/Glutamine Cycle in Adult Glia Controls Motor Activity and Seizures in Drosophila.

成年神经胶质细胞谷氨酸/GABA/谷氨酰胺循环的转录调节控制果蝇的运动活动和癫痫发作。

• 发表时间: 2019
• 作者: Mazaud, David;Kottler, Benjamin;Gonçalves;Proelss, Sandra;Tüchler, Nadine;Deneubourg, Celine;Yuasa, Yoshihiro;Diebold, Celine;Jungbluth, Heinz;Lai, Eric C;Hirth, Frank;Giangrande, Angela;Fanto, Manolis
• 通讯作者: Fanto, Manolis

IsoSCM: improved and alternative 3' UTR annotation using multiple change-point inference.

IsoSCM：使用多个变化点推理改进和替代 3 UTR 注释。

• 发表时间: 2015-01
• 作者: Shenker, Sol;Miura, Pedro;Sanfilippo, Piero;Lai, Eric C
• 通讯作者: Lai, Eric C

The Hippo pathway regulates hematopoiesis in Drosophila melanogaster.

Hippo 途径调节果蝇的造血作用。

• 发表时间: 2014-11-17
• 作者: Milton, Claire C;Grusche, Felix A;Degoutin, Joffrey L;Yu, Eefang;Dai, Qi;Lai, Eric C;Harvey, Kieran F
• 通讯作者: Harvey, Kieran F