Systematic mapping and prediction of gene-enhancer connections
Systematic mapping and prediction of gene-enhancer connections
批准号:
10555913
负责人:
JESSE M ENGREITZ
金额:
$1.93万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-01 至 2023-02-28
关键词:
3-DimensionalAddressAffectAllelesArchitectureB-LymphocytesBiologicalBiological ModelsBiologyCRISPR interferenceCRISPR/Cas technologyCell LineCell modelCell physiologyCellsChIP-seqChromatinChromosome MappingChromosomesCollaborationsComplexComputer ModelsDNase I hypersensitive sites sequencingDataData ElementDevelopmentDiseaseDistalEnhancersEnvironmentExperimental ModelsGene ExpressionGene Expression RegulationGenesGenetic DiseasesGenetic VariationGenomeGenomicsHeritabilityHi-CHumanHuman Cell LineHuman GenomeImmuneImmune System DiseasesIndividualLaboratoriesLeadLigandsLocationMapsMeasuresMedicineMethodsModelingModernizationMolecularMolecular ConformationPhasePlayPropertyRegulationRegulator GenesRegulatory ElementResearchRoleScienceSingle Nucleotide PolymorphismSpecific qualifier valueSpecificitySystemT-LymphocyteTestingUnited States National Institutes of HealthUniversitiesUntranslated RNAUpdateVariantWorkbasecareercell typecollaborative environmentdisorder riskexperimental studygenetic variantgenome editinggenome wide association studygenome-widehuman diseaseinsightmonocytenetwork architecturenovelpleiotropismpredictive toolspromotersystem architecturetherapeutic developmenttoolworking group
中文摘要
现代生物学中的一个基本挑战是确定控制基因表达的非编码调控元件(RE)。
基因表达,这可以解释成千上万的非编码遗传变异,
通过全基因组关联研究(GWAS)发现与人类疾病相关的基因。解释
RE和非编码基因变异的功能一直是一个挑战,因为我们缺乏能力,
系统地干扰RE在基因组中的天然位置。为了应对这一挑战,我最近
开发了一种高通量的方法来定位数千个RE在其天然基因组中的功能,
背景并测量其对基因表达的定量影响(CRISPRi平铺)。我还写了一本小说
基于染色质状态和3D图谱的建模和预测基因-RE连接的分析方法
折页.总之,这些进步促使制定一项战略,以便系统地绘制所有可再生能源的地图,
控制任何给定细胞类型中的任何给定基因。在K99阶段,我建议:(i)将CRISPRi平铺应用于地图
~ 6,000个额外的基因-RE连接,以及(ii)使用这些数据来扩展和优化模型以预测
基因-RE连接从染色质状态。我将使用人类免疫细胞作为模型系统进行比较
预测细胞类型。在R 00阶段,我将应用这些工具(iii)描述网络的特征
构建跨越数百种细胞类型的基因-RE连接,以及(iv)编辑单核苷酸变体
通过细胞模型中的模型来识别它们,以表征它们对基因表达的影响。所有这些
目的将提供深入了解基因-RE连接的机制和架构,
绘制任何细胞类型中的基因-RE连接,并揭示常见疾病的潜在机制。
斯坦福大学是我独立实验室的理想环境,提供了所有的设施
所需的拟议研究和丰富的跨学科环境的合作研究。在一起,
这些目标将在调控基因组学和疾病的界面上开启我的独立科学生涯
遗传学
英文摘要
A fundamental challenge in modern biology is to identify the noncoding regulatory elements (REs) that control
gene expression, which could inform the interpretation of the thousands of noncoding genetic variants
associated with human diseases through genome-wide association studies (GWAS). Interpreting the
functions of REs and noncoding genetic variants has been challenging because we have lacked the ability
to systematically perturb REs in their native locations in the genome. To address this challenge, I recently
developed a high-throughput method to map the functions of thousands of REs in their native genomic
contexts and measure their quantitative effects on gene expression (CRISPRi tiling). I also developed a novel
analytical approach to model and predict gene-RE connections based on maps of chromatin state and 3D
folding. Together, these advances motivate a strategy to allow systematic mapping of all of the REs that
control any given gene in any given cell type. In the K99 phase, I propose to: (i) apply CRISPRi tiling to map
~6,000 additional gene-RE connections, and (ii) use these data to extend and optimize a model to predict
gene-RE connections from chromatin state. I will use human immune cells as a model system to compare
predictions across cell types. In the R00 phase, I will apply these tools to (iii) characterize the network
architecture of gene-RE connections across hundreds of cell types, and (iv) edit single-nucleotide variants
identified by the model in cellular models to characterize their effects on gene expression. Together, these
aims will provide insights into the mechanisms and architecture of gene-RE connectivity, generate tools for
mapping gene-RE connectivity in any cell type, and reveal mechanisms underlying common diseases.
Stanford University is an ideal environment for my independent laboratory, providing all of the facilities
needed for the proposed research and a rich interdisciplinary environment for collaborative studies. Together,
these aims will launch my independent scientific career at the interface of regulatory genomics and disease
genetics.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10446856
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批准号:10591585
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Systematic mapping and prediction of gene-enhancer connections
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批准号:10318508
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资助金额:$0.15万
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依托单位:
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批准号:10633286
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资助金额:$188.25万
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依托单位:
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批准号:10480918
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资助金额:$220.36万
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财政年份:2021
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依托单位:
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批准号:10295739
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项目类别:
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依托单位:
Mapping enhancer-gene regulation in single cells to connect genetic variants to target genes and cell types
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批准号:10434907
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项目类别:
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资助金额:$47.31万
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负责人:JESSE M ENGREITZ
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Systematic mapping and prediction of gene-enhancer connections
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批准号:10153858
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负责人:JESSE M ENGREITZ
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依托单位:
Systematic mapping and prediction of gene-enhancer connections
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资助金额:$24.14万
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依托单位:
Mapping enhancer-gene regulation in single cells to connect genetic variants to target genes and cell types
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批准号:10251161
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资助金额:$47.31万
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Mapping enhancer-gene regulation in single cells to connect genetic variants to target genes and cell types
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批准号:10657459
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项目类别:
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资助金额:$47.31万
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财政年份:2020
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负责人:JESSE M ENGREITZ
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依托单位:
海外基金