Super-enhancer structure defines a signature of inflammatory bowel disease (IBD)

描述（由申请人提供）：本提案的目标是通过整合全基因组关联研究（GWAS）与人类免疫系统中的染色质修饰信息，破译炎症性肠病（IBD）的遗传基础。越来越多的证据表明，IBD是由遗传易感宿主对肠道微生物的不适当炎症反应引起的。在复杂疾病中，GWAS方法在IBD中取得了成功，鉴定了数百个非重叠遗传风险位点。然而，大多数这些疾病相关的DNA变异属于基因组的基因沙漠部分，使其功能评估复杂化。现在有压倒性的证据表明，非编码疾病相关的DNA变异破坏了相关细胞类型中关键调控元件的作用。由于活性调控元件的基因组坐标可以使用独特的染色质特征绘制，因此相关细胞类型中染色质修饰的全基因组分析可以用于精确定位破坏活性调控元件的DNA变体。 最近的两项研究发现了一种新的增强子，它出现在非常大的基因组结构域中。这些区域最初被称为“超级增强子”。超级增强子结构域出现在多种细胞类型中的关键身份基因处。引人注目的是，这些增强子结构域比典型的较短增强子对干扰如转录因子的丢失更敏感。 由于超级增强子对扰动的脆弱性，我假设相关免疫细胞的超级增强子结构域含有IBD相关的DNA变体。为了验证这一假设，在本提案的目标1中，我将描述人类免疫系统的超级增强子结构。我将首先开发一种无监督的机器学习技术，根据不同免疫细胞中的组蛋白乙酰化（H3K27Ac）数据绘制超级增强子结构。使用这种技术，我接下来将描绘免疫细胞中的细胞类型特异性增强子结构域，并研究细胞类型与其超级增强子结构之间的关系。在本提案的目标2中，我将研究IBD相关DNA变体在最相关免疫细胞的超级增强子内的富集。然后，我将这些变异与它们调节的基因和途径联系起来，并利用基因表达和长距离染色质相互作用数据集在疾病中受到影响。这些目标的完成，沿着与本提案相关的培训机会，将为我作为独立调查员的职业生涯奠定必要的基础。

DESCRIPTION (provided by applicant): The goal of this proposal is to decipher the genetic basis of inflammatory bowel disease (IBD) by integrating genome-wide association studies (GWAS) with the chromatin modification information in human immune system. Accumulating evidence suggests that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Among complex diseases, GWAS methods have been successful in IBD, identifying hundreds of non-overlapping genetic risk loci. However, the majority of these disease-associated DNA variants fall into the gene-desert part of the genome, complicating their functional evaluation. There is now overwhelming evidence that the noncoding disease-associated DNA variants disrupt the action of key regulatory elements in relevant cell types. Since genomic coordinates of active regulatory elements can be charted using unique chromatin features, genome-wide profiling of chromatin modifications in relevant cell types can be used to pinpoint to DNA variants disrupting active regulatory elements. Two recent studies discovered a novel kind of enhancers that occurs within exceptionally large genomic domains. These regions were initially dubbed as 'super-enhancers'. Super-enhancer domains occur at key identity genes in a variety of cell types. Strikingly, these enhancer domains are more sensitive to perturbation such as loss of transcription factors than typical shorter enhancers. Because of the fragility of super-enhancers to perturbation, I postulate that super-enhancer domains of relevant immune cells harbor IBD-associated DNA variants. To test this hypothesis, in Aim 1 of this proposal, I will characterize super-enhancer structures of the human immune system. I will first develop an unsupervised machine learning technique to chart super-enhancer structures from histone acetylation (H3K27Ac) data in diverse immune cells. Using this technique, I will next delineate cell type- specific enhancer domains in the immune cells and investigate the relationship among cells types with respect to their super-enhancer structures. In Aim 2 of this proposal, I will investigate the enrichment of IBD-associated DNA variants within the super-enhancers of the most relevant immune cells. I then link these variants to genes and pathways that they regulate and are affected in disease utilizing gene expression and long-range chromatin interaction datasets. Completion of these aims, along with training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.