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

将 Capture-HiC 与组学时间过程数据相结合，揭示疾病遗传变异调节的调控相互作用

• 批准号: MR/N00017X/1
• 负责人: Magnus Rattray
• 金额: $ 77.49万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN00017X%2F1
• 关键词: Integrating; Capture; HiC; omic; time

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.

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) 发现了许多与 RA 相关的遗传差异，其中分析大型遗传数据集，以统计方式将人群中的遗传变化（通常是单核苷酸差异，称为 SNP）与疾病风险关联起来。然而，为了取得进展，现在重要的是提高我们对这些与疾病相关的 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。了解这些与疾病相关的 SNP 的作用的一个主要障碍是，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，增强子区域是 DNA 的远端控制区域，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接近。申请人之一彼得·弗雷泽 (Peter Fraser) 是研究 DNA 如何折叠的领先专家，并开发了新颖的实验方法来对其进行测试。这使我们能够研究与 RA 相关的 DNA 区域如何相互作用并控制人类细胞中的基因。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随时间的测量结合起来。我们将特别关注受刺激的 T 细胞，这些细胞参与免疫系统，并被认为是 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-启动子相互作用来调节基因表达。这些模型将使我们能够更好地了解调节蛋白（称为转录因子）如何与增强子和启动子处的 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，其中已经有遗传数据（SNP 调用），以测试我们在通过分析确定的 SNP 中观察到的自然遗传变异是否确实对增强子活性或增强子-启动子相互作用产生强烈影响。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。该项目将领先的 RA 遗传学小组与领先的分子生物学小组和领先的数学建模师紧密合作，利用最新的知识来深入了解导致 RA 的基因功能。

项目成果

Using functional genomics to advance the understanding of psoriatic arthritis.

使用功能基因组学来提高对银屑病关节炎的理解。

• DOI: 10.1093/rheumatology/keaa283
• 发表时间: 2020-11-01
• 期刊: Rheumatology (Oxford, England)
• 作者: Shi C;Rattray M;Barton A;Bowes J;Orozco G
• 通讯作者: Orozco G

POS0035 GENE REGULATION IN T-CELLS FROM PsA PATIENTS DIFFERS BETWEEN PERIPHERAL BLOOD AND THE INFLAMED JOINTS: IMPLICATIONS FOR THE INTERPRETATION OF GWAS SIGNALS

POS0035 PSA 患者 T 细胞中的基因调控在外周血液和发炎关节之间存在差异：对 GWAS 信号解释的影响

• DOI: 10.1136/annrheumdis-2022-eular.567
• 发表时间: 2022
• 期刊: Annals of the Rheumatic Diseases
• 影响因子: 27.4
• 作者: Shi C

HiChIP-Peaks: A HiChIP peak calling algorithm

HiChIP-Peaks：HiChIP 峰值检出算法

• DOI: 10.1101/682781
• 发表时间: 2019
• 作者: Shi C

Inferring the perturbation time from biological time course data.

• DOI: 10.1093/bioinformatics/btw329
• 发表时间: 2016-10-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Yang J;Penfold CA;Grant MR;Rattray M
• 通讯作者: Rattray M

OP0099 UNVEILING THE COMPLEX GENE REGULATORY MECHANISMS OF PSORIATIC ARTHRITIS THROUGH CHROMATIN CONFORMATION, GENE EXPRESSION AND CHROMATIN ACCESSIBILITY ANALYSIS IN PRIMARY CELLS

OP0099 通过原代细胞染色质构象、基因表达和染色质可及性分析揭示银屑病关节炎的复杂基因调控机制

• DOI: 10.1136/annrheumdis-2023-eular.981
• 发表时间: 2023
• 作者: Shi C