A High-Resolution Enhancer Atlas of the Developing Forebrain
前脑发育的高分辨率增强器图谱
基本信息
- 批准号:7694253
- 负责人:
- 金额:$ 55.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-30 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAtlasesAutomobile DrivingBinding SitesBiological AssayBrainBrain DiseasesCatalogingCatalogsCharacteristicsCodeCollectionCommunitiesComputing MethodologiesCoupledDNADNA SequenceDataData SetDatabasesDepositionDevelopmentDistantElementsEmbryoEnhancersFunctional RNAFundingGene ExpressionGenerationsGenesGeneticGenomeGenomicsGoalsHereditary DiseaseHistologyHumanHuman DevelopmentHuman GeneticsHuman GenomeIndiumInternetLaboratoriesLinkLocationMapsMethodsMusMutationMutation DetectionNational Human Genome Research InstituteNucleic Acid Regulatory SequencesParaffinPatternPropertyProsencephalonReagentRegulationRegulatory ElementReporterResearch PersonnelResolutionResourcesRoleSpecificitySpecimenTestingTissuesTrainingTranscriptional RegulationTransgenic MiceVocabularybasebeta-Galactosidasecomparativecomputerized toolsdevelopmental diseasegenome sequencinggenome-wideimprovedin vivomarkov modelprogramspublic health relevancetranscription factorvertebrate genomeweb site
项目摘要
DESCRIPTION (provided by applicant): Development of the mammalian forebrain critically depends on the dynamic but precise spatial and temporal control of gene expression. While ongoing public efforts are actively mapping gene expression patterns on a genomic scale, the transcriptional enhancer sequences that drive these exquisite patterns remain poorly defined. Comparative genomic methods increasingly enable relatively confident predictions of the location of putative distant-acting enhancers, but a deeper understanding of their exact tissue-specificities has yet to emerge due to the lack of high-quality collections of experimental datasets. In preliminary studies, we have coupled comparative genomics to a high-throughput mouse transgenic reporter assay and identified more than 100 distant-acting enhancer sequences that reproducibly drive in vivo expression in the developing forebrain and are in many cases located near genes known to be required for brain development. Here we propose to exploit this unique enhancer collection to produce a first-generation high-resolution cis-regulatory atlas of the developing forebrain. This goal will be achieved through detailed histological and neuroanatomical analysis of all forebrain enhancers identified so far. We will then bin elements that drive identical patterns within the forebrain and computationally define their common transcription factor binding sites and other sequence features and use this forebrain cis-regulatory code to generate genome-wide enhancer catalogues. The validity of such predictions will be determined through the testing of 200 of these elements in transgenic mice. High-resolution data and annotations from the initial atlas as well as enhancers generated through our predictions will be made available to the community through an existing web portal, allowing researchers to access this data to a) understand the regulation of forebrain genes, b) identify candidate regions for regulatory mutation screens in human genetic disorders, c) retrieve tissue-specific reagents for a variety of downstream experimental applications, d) download data sets for computational or experimental regulatory studies. PUBLIC HEALTH RELEVANCE Efforts to understand how genes control the development of the human brain have focused on when and where genes are active during development, but have largely ignored the role of genetic switches ("enhancers") that control these very activities. Here we propose to map the precise activity of several hundred enhancers in the brain to aid in predicting additional forebrain enhancer in the entire human genome and thereby provide the scientific community with a "brain enhancer atlas". These studies are likely to have implications in defining the role of these switches for normal brain function and how they go awry in human brain diseases.
描述(由申请人提供):哺乳动物前脑的开发在很大程度上取决于基因表达的动态空间和时间控制。 虽然持续的公众努力是在基因组量表上积极绘制基因表达模式,但驱动这些精致模式的转录增强子序列仍然很差。 比较基因组方法越来越多地使人们能够对推定的遥远作用增强剂的位置进行相对自信的预测,但是由于缺乏高质量的实验数据集集合,对它们确切的组织特异性的更深入了解尚未出现。 在初步研究中,我们将比较基因组学与高通量小鼠转基因报告基因测定法耦合,并确定了100多个远程作用增强子序列,这些序列可重复地在发育中的前脑中驱动体内表达,并且在许多情况下是脑发育所需的基因所需的许多情况。 在这里,我们建议利用这一独特的增强子收集,以生成发展前脑的第一代高分辨率顺式调节地图集。 该目标将通过迄今为止确定的所有前脑增强剂的详细组织学和神经解剖学分析来实现。 然后,我们将bin元素在前脑内驱动相同的模式并在计算上定义其常见的转录因子结合位点和其他序列特征,并使用此前脑顺式调节代码来生成全基因组增强子目录。 这种预测的有效性将通过在转基因小鼠中测试这些元素的200个元素来确定。 High-resolution data and annotations from the initial atlas as well as enhancers generated through our predictions will be made available to the community through an existing web portal, allowing researchers to access this data to a) understand the regulation of forebrain genes, b) identify candidate regions for regulatory mutation screens in human genetic disorders, c) retrieve tissue-specific reagents for a variety of downstream experimental applications, d) download data sets for计算或实验监管研究。 公共卫生相关性的努力以了解基因如何控制人脑的发展,集中在基因在发育过程中何时何地活跃,但在很大程度上忽略了控制这些活动的遗传转换(“增强剂”)的作用。 在这里,我们建议绘制大脑中数百个增强剂的精确活性,以帮助预测整个人类基因组中的其他前脑增强子,从而为科学界提供“脑增强剂Atlas”。 这些研究可能对定义这些开关对正常脑功能的作用以及它们在人脑疾病中的问题有影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Len Alexander Pennacchio其他文献
Len Alexander Pennacchio的其他文献
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