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

描述(申请人提供)：这项建议的目标是通过整合全基因组关联研究(GWAS)和人类免疫系统中的染色质修饰信息来破译炎症性肠病(IBD)的遗传基础。越来越多的证据表明，IBD是由于遗传易感宿主对肠道微生物的不适当炎症反应造成的。在复杂疾病中，GWAS方法已经在IBD中取得了成功，识别了数百个不重叠的遗传风险基因座。然而，这些与疾病相关的DNA变体中的大多数落入基因组的基因沙漠部分，使它们的功能评估变得复杂。现在有压倒性的证据表明，与疾病相关的非编码DNA变体扰乱了相关细胞类型中关键调控元件的活动。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出来，因此可以使用相关细胞类型中染色质修改的全基因组图谱来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剂，它发生在非常大的基因组结构域中。这些地区最初被称为“超级增强剂”。超级增强子域出现在各种细胞类型的关键身份基因上。值得注意的是，这些增强子结构域对转录因子丢失等干扰比典型的较短增强子更敏感。由于超级增强子对扰动的脆弱性，我推测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，在这项提议的目标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，根据组蛋白乙酰化(H3K27Ac)数据绘制不同免疫细胞中的超级增强子结构图。使用这项技术，我接下来将描绘免疫细胞中细胞类型特定的增强子结构域，并研究细胞类型与其超级增强子结构之间的关系。在这项提案的目标2中，我将研究与IBD相关的DNA变体在最相关的免疫细胞的超级增强剂中的浓缩。然后，我利用基因表达和远程染色质相互作用数据集，将这些变体与它们调节并在疾病中受到影响的基因和途径联系起来。完成这些目标，以及与这项提议相关的培训机会，将为我作为一名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.