Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
基本信息
- 批准号:7886117
- 负责人:
- 金额:$ 30.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlternative SplicingAntibodiesAntigensAutoimmune ProcessBindingBiochemicalBiochemical GeneticsBiological ProcessCell Culture SystemCellsChromatinChromatin Remodeling FactorComplexCouplingDataDerivation procedureDevelopmentDiseaseEpitopesExonsFamilyFundingGene TargetingGenesGeneticGenetic TranscriptionGenomicsGoalsHDAC2 geneHistone H3HistonesIndividualKnock-in MouseLinkLocationMeasuresMediatingMediator of activation proteinModelingModificationMolecularMusMutation AnalysisNF1 geneNatureNeuraxisNeurodegenerative DisordersNeurofibromatosesNeurofibromatosis 1NeurogliaNeurologicNeuronal DifferentiationNeuronsNuclear ExtractPathogenesisPlayPoint MutationPopulationProcessPromoter RegionsProteinsRNA InterferenceRNA SplicingRegulationRoleSequence AnalysisSignal TransductionSpecificitySyndromeSystemTestingTimeTissuesTranscription ElongationUndifferentiatedYeastsbasecell typechromatin immunoprecipitationembryonic stem cellhistone deacetylase 2insightinterestmRNA Precursormutantnervous system developmentnovelnovel strategiespublic health relevanceresearch studytoolyeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how alternative splicing is regulated in the mammalian central nervous system (CNS). Studies carried out during the previous funding period established the Hu family of paraneoplastic neurologic disease (PND) antigens in neurons as alternative splicing regulators. More recently, preliminary data from a yeast two-hybrid screen uncovered a potential role for Hu proteins as mediators that link transcription with splicing. Specifically, HuC interacts with histone H3 and histone deacetylase HDAC2. Importantly, Hu proteins associate with RNAPII engaged in elongation and expression of Hu proteins correlates with higher level of acetylated H3 and H4 in an internal region of the Neurofibromatosis Type 1 (NF1) gene surrounding the alternatively spliced exon 23a. The central goal of this proposal is to test the hypothesis that Hu proteins regulate splicing in a co-transcriptional manner by directly interacting with chromatin bound histone H3 and/or the chromatin remodeling factor HDAC2. To define the molecular basis of the mechanisms through which these interactions regulate pre-mRNA splicing in CNS neurons, three specific aims will be pursued. In aim I, a robust mouse system will be established for the derivation of homogeneous CNS neurons from mouse ES cells to study neuron-specific alternative splicing. This system will allow us to combine genetic and biochemical approaches to investigate splicing regulation in neuronal cells. In aim II, the potential involvement of the transcription machinery in Hu-mediated regulation of alternative splicing in neurons will be examined. The specificity of the Hu-HDAC interaction will be determined and deletion and point mutational analysis will be carried out to define the nature of these interactions. Further studies will test whether Hu proteins are associated with the promoter region of NF1 and other genes in neurons. In aim III, the functional consequences of the Hu-HDAC/H3 interactions in Hu-mediated alternative splicing in neurons will be determined. Using exon 23a of the NF1 pre-mRNA as the substrate, the effect of transcription elongation rate on alternative splicing will be examined. These studies will provide fundamental insights into the mechanisms that control tissue-specific, particularly neuron-specific, alternative RNA splicing and coupling of transcription and splicing. The CNS neuronal differentiation system to be developed will serve as a valuable new alternative model in studies of neuron-specific splicing regulation.
PUBLIC HEALTH RELEVANCE: Hu proteins are autoimmune antigens of a neurodegenerative disease called Hu syndrome. The proposed studies will investigate how these proteins regulate expression of neuron-specific proteins. These studies will provide not only significant insights into the role of Hu proteins in the development and function of neurons, but also important hints of pathogenesis of the Hu syndrome.
描述(申请人提供):该项目的长期目标是了解哺乳动物中枢神经系统(CNS)中选择性剪接是如何调控的。在上一次资助期间进行的研究确定了胡氏家族的副肿瘤性神经疾病(PND)抗原在神经元中作为替代剪接调节因子。最近,来自酵母双杂交筛查的初步数据揭示了Hu蛋白作为连接转录和剪接的中介的潜在作用。具体地说,Huc与组蛋白H3和组蛋白脱乙酰酶HDAC2相互作用。重要的是,与RNAPII相关的HU蛋白参与延伸,HU蛋白的表达与神经纤维瘤病1型(NF1)基因23a外显子周围较高水平的乙酰化H3和H4相关。这一建议的中心目标是检验HU蛋白通过直接与染色质结合的组蛋白H3和/或染色质重塑因子HDAC2相互作用以协同转录的方式调节剪接的假设。为了确定这些相互作用调节中枢神经系统神经元中前mRNA剪接的机制的分子基础,将追求三个特定的目标。在目标I中,将建立一个健壮的小鼠系统,用于从小鼠ES细胞中获得同质的中枢神经系统神经元,以研究神经元特异性的选择性剪接。这个系统将使我们能够结合遗传和生化方法来研究神经细胞的剪接调控。在AIM II中,将研究转录机制在Hu介导的神经元选择性剪接调控中的潜在参与。将确定HU-HDAC相互作用的特异性,并将进行缺失和点突变分析,以确定这些相互作用的性质。进一步的研究将测试Hu蛋白是否与神经元中NF1和其他基因的启动子区域有关。在目标III中,将确定Hu-HDAC/H3相互作用在Hu介导的神经元选择性剪接中的功能后果。以NF1前体基因外显子23a为底物,考察转录延伸率对选择性剪接的影响。这些研究将为控制组织特异性、特别是神经元特异性的替代RNA剪接以及转录和剪接的耦合提供基本的见解。即将建立的中枢神经系统神经元分化系统将为神经元特异性剪接调控的研究提供一种有价值的新模型。
公共卫生相关性:HU蛋白是一种名为HU综合征的神经退行性疾病的自身免疫抗原。这项拟议的研究将调查这些蛋白质如何调节神经元特异性蛋白质的表达。这些研究不仅将对HU蛋白在神经元发育和功能中的作用提供重要的见解,也将为HU综合征的发病机制提供重要的线索。
项目成果
期刊论文数量(0)
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HUA LOU其他文献
HUA LOU的其他文献
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{{ truncateString('HUA LOU', 18)}}的其他基金
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
8492172 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
7252680 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
8286996 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
6895448 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
7812578 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
8015984 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
7082879 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
Hu proteins as novel splicing regulators in neurons
Hu 蛋白作为神经元中新型剪接调节因子
- 批准号:
6812519 - 财政年份:2004
- 资助金额:
$ 30.44万 - 项目类别:
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