Integrating Capture-HiC with omic time course data to uncover the regulatory interactions modulated by genetic variation in disease

类风湿性关节炎（RA）是最常见的慢性炎症性疾病之一。通过全基因组关联研究（GWAS）发现了与类风湿性关节炎相关的许多遗传差异，该研究分析了大量遗传数据集，以统计地将人群中的遗传变化（通常是单核苷酸的差异，称为snp）与疾病风险联系起来。然而，为了取得进展，现在重要的是提高我们对这些疾病相关snp如何影响细胞和组织功能的理解，以便我们能够更好地了解疾病机制并最终开发出更有效的药物。了解这些疾病相关snp影响的一个主要障碍是，就基因组的线性DNA序列而言，其中许多snp远离蛋白质编码基因（称为启动子）的主要控制区域。有强有力的证据表明，其中一些snp位于增强子区域，这些增强子区域是DNA的远端控制区，通过DNA序列的环化与启动子接触，即这些增强子区域在DNA序列上看起来很远，但在物理空间上可能很近。其中一位申请者彼得·弗雷泽（Peter Fraser）是研究DNA折叠方式的权威专家，他开发了新的实验方法来测试DNA折叠方式。这使我们能够研究与类风湿关节炎相关的DNA区域如何在人类细胞中相互作用和控制基因。在这个项目中，我们将把这项技术与人类细胞中基因活性和增强子活性的测量结合起来。我们将特别关注受刺激的t细胞，这些细胞参与免疫系统，并且已知是RA疾病进展的重要决定因素。我们将利用这些数据建立数学模型，描述t细胞如何通过增强子活性和增强子-启动子相互作用调节基因表达。这些模型将使我们更好地了解被称为转录因子的调节蛋白如何在增强子和启动子处与DNA结合，从而打开或关闭基因。最后，我们将对来自健康人类志愿者的t细胞进行实验，其中遗传数据（SNP调用）已经可用，以测试我们在分析中发现的SNP中观察到的自然遗传变异是否对增强子活性或增强子-启动子相互作用有强烈影响。这将为这些snp如何调节特定基因提供强有力的证据，我们将研究这些基因所属的下游细胞途径。该项目将一个领先的RA遗传学小组与一个领先的分子生物学小组和一个领先的数学建模小组紧密合作，利用最新的知识来深入了解导致RA的基因的功能。

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases. A number of genetic differences related to RA have been discovered through Genome Wide Association Studies (GWAS) where large genetic datasets are analysed to statistically associate genetic changes in the human population (usually differences at single nucleotides, called SNPs) with disease risk. However, to make progress it is now important to improve our understanding of how these disease-associated SNPs affect the functions of cells and tissues, so that we can better understand the disease mechanism and ultimately develop more effective medicines. A major obstacle to understanding the effect of these disease-associated SNPs is that many of them lie far from the main control regions of protein-coding genes (known as promoters) in terms of the linear DNA sequence of the genome. There is strong evidence that some of these SNPs lie in enhancer regions which are distal control regions of DNA that come into contact with promoters through looping of the DNA sequence, i.e. these enhancer regions appear distant in terms of DNA sequence but may be close in physical space. One of the applicants, Peter Fraser, is a leading expert in investigating how DNA folds and has developed novel experimental methods to allow this to be tested. This allows us to investigate how the DNA regions associated with RA interact and control genes in human cells. In this project we will combine this technique with measurements of gene activity and enhancer activity in human cells over time. We will look specifically at stimulated T-cells, cells which are involved in the immune system and are known to be important determinants of RA disease progression. We will use these data to build mathematical models describing how T-cells regulate gene expression through enhancer activity and enhancer-promoter interaction. These models will allow us to better understand how regulatory proteins, called transcription factors, bind to the DNA at enhancers and promoters to turn genes on or off. Finally, we will carry out experiments on T-cells derived from healthy human volunteers where genetic data (SNP calls) are already available to test whether the natural genetic variation we observe at SNPs identified through our analysis do have a strong effect on enhancer activity or enhancer-promoter interactions. This would then provide strong evidence for how these SNPs regulate specific genes and we will investigate the downstream cellular pathways to which these genes belong. The project brings a leading RA genetics group together with a leading molecular biology group and a leading mathematical modeller to work closely together and utilise the most up to date knowledge to gain insight into the function of genes that cause RA.