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
基本信息
- 批准号:10543867
- 负责人:
- 金额:$ 59.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3&apos Untranslated RegionsAffectAmazeAutomobile DrivingBinding SitesBiochemistryBioinformaticsBiologicalBiological AssayBiologyBrainCellsComplexDataDefectDevelopmentDiseaseDrosophila genusEmbryoEngineeringExhibitsFamilyGene ExpressionGenesGeneticGenetic ModelsGenomicsHU ProteinHumanIndividualMalignant NeoplasmsMammalsMediatingMicroRNAsMolecularMolecular BiologyMolecular GeneticsMusMutant Strains MiceNervous SystemNeuronsNeurophysiology - biologic functionOrthologous GeneOutcomePathway interactionsPatternPhenotypePhysiologyPlayPoly APolyadenylationPost-Transcriptional RegulationPre-mRNA Polyadenylation FactorProcessProtein FamilyProtein IsoformsRNA-Binding ProteinsRecording of previous eventsRegulationReporterReporter GenesRepressionRoleSiteSystemTestingTimeTissuesTrans-ActivatorsTranscriptTransgenic OrganismsTranslationsVertebratesWorkcohortcrosslinking and immunoprecipitation sequencingderepressiondisorder subtypeflygenome-widegenomic datahuman diseasehuman embryonic stem cellin vivointerdisciplinary approachinterestmRNA Stabilitymembermorphogensmouse geneticsmouse modelmutantnervous system disorderneuralneurodevelopmentneuromechanismnovelposttranscriptionalprogramstooltranscriptometranscriptome sequencingtrendunpublished works
项目摘要
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
不表达单个3' UTR,而是通过一个3' UTR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
如果它们有能力重塑转录组,那么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。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Alternative polyadenylation in the nervous system: to what lengths will 3' UTR extensions take us?
- DOI:10.1002/bies.201300174
- 发表时间:2014-08
- 期刊:
- 影响因子:0
- 作者:Miura P;Sanfilippo P;Shenker S;Lai EC
- 通讯作者:Lai EC
IsoSCM: improved and alternative 3' UTR annotation using multiple change-point inference.
- DOI:10.1261/rna.046037.114
- 发表时间:2015-01
- 期刊:
- 影响因子:0
- 作者:Shenker S;Miura P;Sanfilippo P;Lai EC
- 通讯作者:Lai EC
The Hippo pathway regulates hematopoiesis in Drosophila melanogaster.
- DOI:10.1016/j.cub.2014.10.031
- 发表时间:2014-11-17
- 期刊:
- 影响因子:9.2
- 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.
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.
对果蝇 miRNA 性别二态性表达的全基因组调查发现,类固醇激素诱导的 miRNA let-7 是性别认同的调节因子。
- DOI:10.1534/genetics.114.169268
- 发表时间:2014-10
- 期刊:
- 影响因子:3.3
- 作者:Fagegaltier D;König A;Gordon A;Lai EC;Gingeras TR;Hannon GJ;Shcherbata HR
- 通讯作者:Shcherbata HR
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{{ truncateString('Eric C Lai', 18)}}的其他基金
Essential roles for RNAi/hpRNAs to resolve intragenomic conflicts in the male germline
RNAi/hpRNA 在解决雄性种系基因组内冲突中的重要作用
- 批准号:
10617394 - 财政年份:2022
- 资助金额:
$ 59.16万 - 项目类别:
Essential roles for RNAi/hpRNAs to resolve intragenomic conflicts in the male germline
RNAi/hpRNA 在解决雄性种系基因组内冲突中的重要作用
- 批准号:
10467212 - 财政年份:2022
- 资助金额:
$ 59.16万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 59.16万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 59.16万 - 项目类别:
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:
8698063 - 财政年份:2014
- 资助金额:
$ 59.16万 - 项目类别:
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:
8791352 - 财政年份:2014
- 资助金额:
$ 59.16万 - 项目类别:
BEN factors are conserved CSL co-repressors in Notch-mediated neural development
BEN 因子是 Notch 介导的神经发育中保守的 CSL 共抑制因子
- 批准号:
8325028 - 财政年份:2011
- 资助金额:
$ 59.16万 - 项目类别:
BEN factors are conserved CSL co-repressors in Notch-mediated neural development
BEN 因子是 Notch 介导的神经发育中保守的 CSL 共抑制因子
- 批准号:
8730239 - 财政年份:2011
- 资助金额:
$ 59.16万 - 项目类别:
BEN factors are conserved CSL co-repressors in Notch-mediated neural development
BEN 因子是 Notch 介导的神经发育中保守的 CSL 共抑制因子
- 批准号:
8535849 - 财政年份:2011
- 资助金额:
$ 59.16万 - 项目类别:
BEN factors are conserved CSL co-repressors in Notch-mediated neural development
BEN 因子是 Notch 介导的神经发育中保守的 CSL 共抑制因子
- 批准号:
8239327 - 财政年份:2011
- 资助金额:
$ 59.16万 - 项目类别:
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