Functional characterization of blood cell associated regulatory GWAS hits
血细胞相关监管 GWAS 命中的功能表征
基本信息
- 批准号:9230428
- 负责人:
- 金额:$ 36.41万
- 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:2014-03-05 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAlgorithmsAllelesBiologicalBlood CellsCD34 geneCatalogsCellsCharacteristicsChromatinComplexCrohn&aposs diseaseDNADNA SequenceDataDiseaseDistalEmployee StrikesEngineeringErythrocytesErythroidFoundationsGene Expression RegulationGenerationsGenetic TranscriptionGenomeGenomicsHematopoieticHumanHypersensitivityIndividualK562 CellsKnock-outLightMediatingModelingModificationMolecularNatureNucleic Acid Regulatory SequencesPhasePhenotypeProbabilityProcessRNARegulationRegulatory ElementRiskRoleSideSiteSurveysT-LymphocyteTechniquesTestingTissuesUntranslated RNAVariantcell typechromatin modificationgenetic variantgenome wide association studygenome-wide analysishomologous recombinationin vivonovelnucleasepromoterpublic health relevancetraittranscription factor
项目摘要
DESCRIPTION (provided by applicant): The vast majority (>90%) of disease- and trait-associated variants emerging from genome-wide association studies (GWAS) lie in non-coding regions of the genome, and currently all but a handful lack molecular mechanisms that explain the observed associations with complex traits. Superimposition of the human regulatory DNA catalogue with GWAS data reveals a striking concentration of disease-associated variation precisely within regulatory DNA regions defined by DNaseI hypersensitive sites. We will fully understand gene regulation and mis-regulation only if we are able to examine genetic variants in their biological chromatin context in otherwise isogenic cells. TALE nuclease (TALEN) platforms can alter the DNA sequence of cells in a precise, targeted manner. We have already established the feasibility of single-TALEN- mediated homologous recombination for efficient knockout of individual regulatory DNA regions. In R21 phase, we will model candidate disease/trait-associated variants in regulatory DNA in vivo using engineered templates at 10 individual regulatory regions. We will test the feasibility and determine the salient operating characteristics of a scalable implementation of a TALEN genomic modification pipeline using K562 cells, and demonstrate knockout feasibility and specific allele insertion in primary hematopoietic cells and document efficiencies. We will test the efficiency of a using single or multiple TALENs flanking an editing site. In the R33 phase, we will scale the TALEN pipeline process to efficiently characterize sites identified in GWAS studies as associated with red blood cell phenotypes. These studies will provide a direct proof for the role of regulatory elements and demonstrate the relevance of GWAS associated SNPs as causative for the observed phenotypes.
描述(由申请人提供):全基因组关联研究(GWAS)中出现的绝大多数(>90%)疾病和性状相关变异位于基因组的非编码区,目前几乎所有变异都缺乏解释观察到的与复杂性状相关性的分子机制。人类调控DNA目录与GWAS数据的叠加揭示了由DNaseI超敏位点定义的调控DNA区域内与疾病相关的变异的惊人浓度。只有当我们能够在其他同基因细胞的生物染色质背景下检查遗传变异时,我们才能完全理解基因调控和错误调控。TALE核酸酶(TALEN)平台可以以精确的靶向方式改变细胞的DNA序列。我们已经建立了单TALEN介导的同源重组用于有效敲除单个调控DNA区域的可行性。在R21阶段,我们将在10个单独的调控区域使用工程化模板在体内对调控DNA中的候选疾病/性状相关变体进行建模。我们将测试可行性,并确定使用K562细胞的TALEN基因组修饰管道的可扩展实施的显著操作特征,并证明敲除可行性和原代造血细胞中的特定等位基因插入以及文件效率。我们将测试使用位于编辑位点侧翼的单个或多个TALEN的效率。在R33阶段,我们将扩展TALEN管道流程,以有效表征GWAS研究中确定的与红细胞表型相关的位点。这些研究将为调控元件的作用提供直接证据,并证明GWAS相关SNP作为观察到的表型的病因的相关性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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JOHN A STAMATOYANNOPOULOS其他文献
JOHN A STAMATOYANNOPOULOS的其他文献
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{{ truncateString('JOHN A STAMATOYANNOPOULOS', 18)}}的其他基金
ENCODE Mapping Center-A Comprehensive Catalog of DNase I Hypersensitive Sites
ENCODE 作图中心 - DNase I 超敏感位点综合目录
- 批准号:
10241208 - 财政年份:2021
- 资助金额:
$ 36.41万 - 项目类别:
ENCODE Mapping Center-A Comprehensive Catalog of DNase I Hypersensitive Sites
ENCODE 作图中心 - DNase I 超敏感位点综合目录
- 批准号:
9247732 - 财政年份:2017
- 资助金额:
$ 36.41万 - 项目类别:
Chromatin Accessibility and Regulatory Network Modulation by Endocrine Disrupters
内分泌干扰物对染色质可及性和调节网络的调节
- 批准号:
9266194 - 财政年份:2016
- 资助金额:
$ 36.41万 - 项目类别:
Functional characterization of blood cell associated regulatory GWAS hits
血细胞相关监管 GWAS 命中的功能表征
- 批准号:
8606650 - 财政年份:2014
- 资助金额:
$ 36.41万 - 项目类别:
High-resolution mapping of DNaseI hypersensitive regulatory DNA in GTEx samples
GTEx 样品中 DNaseI 超敏调节 DNA 的高分辨率图谱
- 批准号:
8841803 - 财政年份:2014
- 资助金额:
$ 36.41万 - 项目类别:
High-resolution mapping of DNaseI hypersensitive regulatory DNA in GTEx samples
GTEx 样品中 DNaseI 超敏调节 DNA 的高分辨率图谱
- 批准号:
9052200 - 财政年份:2014
- 资助金额:
$ 36.41万 - 项目类别:
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