Functional assessment of distal regulatory SNPs associated with type 1 diabetes.

与 1 型糖尿病相关的远端调节 SNP 的功能评估。

• 批准号: 9934717
• 负责人: Raymond David Hawkins
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934717
• 关键词: Address; Asthma; Autoimmune Diseases; Automobile Driving; Binding; Biological Assay; Catalogs; Categories; Cells; ChIP-seq; Chromatin; Code; Crohn' s disease; Data; Disease; Distal; Enhancers; Equilibrium; Etiology; Evaluation; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic study; Genome; Goals; Helper-Inducer T-Lymphocyte; Human; Immune system; Insulin; Insulin-Dependent Diabetes Mellitus; Intercistronic Region; Introns; Light; Linkage Disequilibrium; Location; Maps; Mediating; Methods; Multiple Sclerosis; National Human Genome Research Institute; Nucleic Acid Regulatory Sequences; Pathogenesis; Play; Process; Psoriasis; Regulatory Element; Reporter; Research; Rheumatoid Arthritis; Series; Single Nucleotide Polymorphism; T cell differentiation; T cell regulation; T-Lymphocyte; Technology; Testing; Time; Twin Multiple Birth; Ulcerative Colitis; Validation; Variant; base; causal variant; cell type; genome wide association study; genome-wide; high throughput screening; innovation; next generation sequencing; public health relevance; risk variant; trait; transcription factor

 DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease resulting in the loss of insulin- producing cells. Genetic studies, including those in twins, sugget a strong genetic basis for this disease. Genome-wide association studies (GWASs) have produced large numbers of T1D-associated single-nucleotide polymorphisms (SNPs), but often fail to determine a causative mutation. This may be due to the complexity of the disease; or in part, due to many associated SNPs lying outside of gene coding regions. A recent assessment of GWASs illustrated that 45% of disease or trait associated SNPs fell in introns, while 43% lie in intergenic regions. Global methods for determining chromatin states have shown that associated SNPs can overlap distal regulatory regions such as enhancers. We have constructed enhancer maps based H3K4me1 localization in isolated, human T cells. We analyzed the T1D-associated SNPs from the NHGRI GWAS catalog for overlap with our global T helper cell enhancer predictions. Using 1000 Genomes data we identified additional SNPs in linkage disequilibrium to expand the number of T1D-associated SNPs at enhancer elements. Goal: Our goal is to functionally validate T1D-associated rSNPs. We will use a series of high- throughput assays and systematic evaluation to determine the most functionally relevant rSNPs. We will also determine the target genes of enhancers overlapping T1D SNPs in order to identify new genes important in the etiology of T1D pathogenesis. We will do so through the following specific aims. Specific Aim 1. Determine the effect of T1D rSNPs on enhancer activity. Specific Aim 2. Determine if TF binding is disrupted at T1D-associated enhancer SNPs. Specific Aim 3. Identification of target genes for enhancers harboring associated SNPs.

 描述（由适用提供）：1型糖尿病（T1D）是一种自身免疫性疾病，导致胰岛素生产细胞的丧失。包括双胞胎在内的遗传研究提出了这种疾病的强大遗传基础。全基因组关联研究（GWASS）已经产生了大量与T1D相关的单核苷酸多态性（SNP），但通常无法确定临界突变。这可能是由于疾病的复杂性。或部分原因是许多相关的SNP位于基因编码区域之外。最近对GWASS的评估表明，45％的疾病或性状相关的SNP落在内含子中，而43％的疾病则位于基因间区域。确定染色质状态的全局方法表明，相关的SNP可以重叠盘状调节区域，例如增强剂。我们已经在分离的人类T细胞中构建了基于H3K4ME1的增强图。我们分析了NHGRI GWAS目录中与T1D相关的SNP，以与我们的全局T辅助细胞增强子预测重叠。使用1000个基因组数据，我们确定了在连锁二极管中的其他SNP，以扩大增强子元素上与T1D相关的SNP的数量。目标：我们的目标是在功能上验证与T1D相关的RSNP。我们将使用一系列的高通量测定法和系统评估来确定功能最相关的RSNP。我们还将确定增强子的靶基因重叠T1D SNP，以确定在T1D发病机理病因中重要的新基因。我们将通过以下特定目标这样做。具体目标1。确定T1D RSNP对增强剂活性的影响。具体目标2。确定在与T1D相关的增强子SNP上是否破坏了TF结合。特定目标3。鉴定具有相关SNP的增强子的靶基因。

项目成果

Epigenomic Landscapes of hESC-Derived Neural Rosettes: Modeling Neural Tube Formation and Diseases.

• DOI: 10.1016/j.celrep.2017.07.036
• 发表时间: 2017-08-08
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Valensisi C;Andrus C;Buckberry S;Doni Jayavelu N;Lund RJ;Lister R;Hawkins RD
• 通讯作者: Hawkins RD