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: 8815410
• 负责人: Terrence S. Furey
• 金额: $ 30.02万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815410
• 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; Functional RNA; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Gene Targeting; Gene-Modified; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; 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; Variant; Work; cell type; chromatin remodeling; cytokine; data integration; epigenetic variation; epigenome; epigenomics; evidence base; genome wide association study; histone modification; improved; macrophage; monocyte; novel diagnostics; novel therapeutics; promoter; public health relevance; 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(申请人提供)：克罗恩病(CD)是两种主要的炎症性肠道疾病之一，是由遗传易感宿主对肠道微生物区系的不适当炎症反应引起的。全基因组关联研究已将163个特异的单核苷酸多态(SNPs)与CD病的发病机制联系起来。在这些区域中，还有5600多个SNPs与标签SNPs处于连锁不平衡(LD)状态，目前尚不清楚这些SNPs中哪些与Cd有关。这些SNP大多映射到基因组的非编码区，这表明因果变异通过改变基因调节元件的活性而导致CD。重要的第一步是确定在镉相关的肠道组织中具有不同调控活性的基因组区域，包括结肠，以及受影响和未受影响的个体之间的细胞，即上皮细胞和免疫细胞。为此，我们从27名CD患者和14名正常对照的结肠组织和免疫细胞，以及从5名CD患者和5名正常对照的结肠分离的巨噬细胞、T细胞和上皮细胞中产生了遗传的、开放的染色质和转录组数据。开放染色质分析确定与所有类型的调控元件相关的核小体耗尽的基因组区域，包括启动子、增强子和沉默因子。虽然这些分析提供了所有调控元件在特定组织或细胞样本中位置的最完整的注释，但缺点是它们无法 确定每个调控元件的精确功能(启动子、增强子、抑制子)。表观基因组学路线图项目和ENCODE项目已经在CD相关组织和免疫细胞中产生了组蛋白修饰数据，当这些数据与我们的数据相结合时，将提供关键的调控注释，并将有助于解释这些可变元件的功能。我们的长期目标是阐明遗传变异导致CD的基因组区域和分子机制。这项建议将通过以下具体目标为这一目标做出贡献：1)在CD患者的结肠组织和免疫细胞中确定具有遗传驱动差异调节活性的基因组区域。将Gwas数据与我们来自分型CD患者和对照的开放染色质和转录组数据相结合，我们将确定CD患者具有不同调控活性的一组基于证据的基因组区域；2)整合来自表观基因组学路线图项目(ERP)和ENCODE项目的表观遗传学数据，以注释CD相关调节区的功能。ERP和ENCODE已经从包括结肠粘膜在内的各种组织和细胞类型(包括单核细胞、T细胞、上皮细胞和非免疫细胞群)中生成了数据。我们将使用这些数据来更好地表征CD相关细胞的调节活动，以及这种活动的细胞特异性。TIS项目将有助于填补我们检测与CD有关的遗传、染色质和转录变异的能力与我们解释该变异最终是如何导致CD的能力之间的差距。