Interpreting molecular role of DNA variants associated with Crohn's Disease through integrative analysis of open chromatin, epigenome and transcriptome data in diverse and relevant tissues and cells

通过对不同相关组织和细胞中开放染色质、表观基因组和转录组数据的综合分析，解释与克罗恩病相关的 DNA 变异的分子作用

• 批准号: 8929246
• 负责人: Terrence S. Furey
• 金额: $ 28.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929246
• 关键词: Adolescent and Young Adult; Affect; Allelic Imbalance; American; Biological Assay; Cells; Chromatin; Chronic; Colon; Crohn' s disease; DNA; Data; Development; Disease; Elements; Enhancers; Enteral; Epigenetic Process; Epithelial; Epithelial Cells; Event; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Gene Targeting; Gene-Modified; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Genomics; Genotype; Goals; Health; Histones; Human; Immune; Individual; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Lead; Link; Linkage Disequilibrium; Maps; Modification; Molecular; Mucous Membrane; Nucleic Acid Regulatory Sequences; Nucleosomes; Pathogenesis; Patients; Play; Population; Predisposition; Quantitative Trait Loci; Regulation; Regulatory Element; Research; Resources; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Site; Specificity; T-Lymphocyte; Tail; Tissue Sample; Tissues; Transcriptional Regulation; Untranslated RNA; Variant; Work; cell type; chromatin remodeling; cytokine; data integration; differential expression; epigenetic variation; epigenome; epigenomics; evidence base; genome wide association study; histone modification; improved; macrophage; monocyte; novel diagnostics; novel therapeutics; promoter; risk variant; stem

DESCRIPTION (provided by applicant): Crohn's disease (CD), one of the two major inflammatory bowel diseases, results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. Genome wide association studies (GWAS) have linked 163 specific single nucleotide polymorphisms (SNPs) to CD disease pathogenesis. Within these regions, there are over 5600 additional SNPs that are in linkage disequilibrium (LD) with the tag SNPs, and it is not known which of these contribute to CD. Most of these SNPs map to non-coding regions of the genome, suggesting that causal variants contribute to CD by modifying gene regulatory element activity. An important first step is to identify genomic regions that have differential regulatory activity in CD-relevant intestinal tissues, including colon, and cells, namely epithelial and immune cells, between affected and unaffected individuals. Towards this end, we have generated genetic, open chromatin, and transcriptome data from the colon tissue and immune cells obtained from 27 CD patients and 14 normal controls, and from macrophages, T cells and epithelial cells isolated from the colons of 5 CD patients and 5 normal controls. Open chromatin assays identify nucleosome-depleted genomic regions that are associated with all types of regulatory elements, including promoters, enhancers, and silencers. While these assays provide the most complete annotation of where all regulatory elements are in a particular tissue or cell sample, a weakness is their inability to identify the precise function (promoter, enhancer, silencer) of each regulatory element. The Epigenomics Roadmap Project and ENCODE Project has generated histone modification data in CD-relevant tissues and immune cells that when integrated with our data will provide critical regulatory annotations and will help explain the functions of these variable elements. Our long-term goal is to elucidate the genomic regions and molecular mechanisms by which genetic variation contributes to CD. This proposal will contribute to this goal through the following specific aims: 1) To identify genomic regions with genetically-driven differential regulatory activity in colon tissue and immune cells of CD patients. Integrating GWAS data with our open chromatin and transcriptome data from genotyped CD patients and controls, we will determine an evidence-based set of genomic regions with differential regulatory activity in CD patients; 2) To integrate epigenetic data from the Epigenomics Roadmap Project (ERP) and the ENCODE project to annotate functions of CD-associated regulatory regions. The ERP and ENCODE have generated data from a wide range of tissues, including colon mucosa, and cell types, including monocytes, T cells, epithelial, and non-immune cell populations. We will use these data to better characterize regulatory activity in CD-relevant cells, and the cell-specificity of this activity. Tis project will help fill the gap between our ability to detect genetic, chromatin, and transcriptiona variation linked to CD and our ability to explain how that variation ultimately contributes to CD.

描述（由申请人提供）：克罗恩病（CD）是两种主要的炎症性肠病之一，是由遗传易感宿主对肠道微生物群的不适当定向炎症反应引起的。全基因组关联研究（GWAS）已将163个特异性单核苷酸多态性（snp）与乳糜泻发病机制联系起来。在这些区域内，还有超过5600个snp与标签snp处于连锁不平衡（LD）状态，目前尚不清楚这些snp中哪些与CD有关。这些snp大多数映射到基因组的非编码区域，这表明因果变异通过改变基因调控元件的活性来促进CD。重要的第一步是确定受影响和未受影响个体之间cd相关肠道组织（包括结肠）和细胞（即上皮细胞和免疫细胞）中具有差异调节活性的基因组区域。为此，我们从27名乳糜泻患者和14名正常对照者的结肠组织和免疫细胞，以及从5名乳糜泻患者和5名正常对照者的结肠中分离的巨噬细胞、T细胞和上皮细胞中获得了遗传、开放染色质和转录组数据。开放染色质分析鉴定核小体缺失的基因组区域，这些区域与所有类型的调控元件相关，包括启动子、增强子和沉默子。虽然这些分析提供了所有调节元件在特定组织或细胞样本中位置的最完整注释，但缺点是它们不能