Epigenomics of SLE

SLE的表观基因组学

• 批准号: 8521081
• 负责人: KATHLEEN E SULLIVAN
• 金额: $ 34.92万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521081
• 关键词: Acetylation; Affect; African American; Age; Alleles; Antibodies; Antigen-Antibody Complex; Antisense RNA; Apoptosis; Apoptotic; Arterial Fatty Streak; Arthritis; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Awareness; Behavior; Binding; Bioinformatics; Biological; Cause of Death; Cells; ChIP-seq; Chronic; Chronic Disease; Clinical; DNA; Data; Databases; Deposition; Disease; Environmental Risk Factor; Epigenetic Process; Etiology; Exanthema; Flare; Foundations; Functional RNA; Functional disorder; Genes; Genetic; Genome; Glomerulonephritis; Goals; Histones; Human; Hybrids; Immune system; Immunologics; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Response; Kidney; Kidney Diseases; Lead; Lesion; Leukocytes; Lupus; Messenger RNA; Molds; Morbidity - disease rate; Mus; Natural History; Nuclear; Organ; Pathologic; Pathway Analysis; Pathway interactions; Patients; Pharmacologic Substance; Physiological Processes; Population; Predisposition; Process; Production; RNA; Role; Sampling; Serositis; Signal Pathway; Stimulus; Structure; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Tissues; Transcription Repressor/Corepressor; Virus; Woman; base; body system; cell type; cohort; disease phenotype; epigenome; epigenomics; experience; histone modification; innovation; macrophage; migration; monocyte; mortality; novel; response; systemic autoimmune disease; transcriptome sequencing; young woman

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. African American women are disproportionately affected and the etiology is believed to be a combination of genetic and environmental factors. The natural history typically includes diverse organ system involvement and a chronic course punctuated by flares. Multiple studies have demonstrated that monocyte function is aberrant in SLE and this is significant because monocytes can persist in tissues as differentiated macrophages and mold adaptive responses, thus producing a cascade of effects as a consequence of their aberrant function. Macrophages form the initial lesion in atheromatous disease, associated with the major cause of death in SLE and macrophage infiltration into the kidney is specifically associated with increased morbidity and mortality. These form the rationale for the study of SLE monocytes. We specifically hypothesize that the SLE disease process drives an altered epigenome in monocytes and this contributes to disease perpetuation and end organ manifestations. An altered potential for expression could lead to aberrant monocyte migration or inflammatory mediator expression. Pathologic responses to common innocuous stimuli, such as viruses could ensue as a result of an altered epigenome. This proposal will examine the epigenetic landscape of SLE monocytes and begin to identify pathways that are associated with altered histone modifications. Two opposing histone marks will be examined by ChIP-Seq, H3K4me2 and H3K27me3. We have preliminary data demonstrating altered H4 acetylation in SLE patient monocytes compared to controls. Network analysis of the gene set with altered histone modifications demonstrated nodes of biological relevance, including known inflammatory pathways. A second epigenetic feature, non-coding RNAs, will be examined on an exploratory basis. Preliminary data demonstrate tissue-specific antisense RNA upstream of the TNF1 gene which is associated with binding of a transcriptional repressor. Long mRNA-like non-coding RNAs will be examined and a novel ChIP-Seq approach, using S9.6, used to explore the structure of the potential regulatory RNAs. The S9.6 antibody will be used to identify DNA:RNA hybrid structures and this will be used to filter the non-coding RNAs identified bioinformatically. One of the major goals of this application is to begin to transition to a mechanistic examination of the alterations to the epigenome. We hypothesize that the disease itself drives most of the alterations to the epigenome, however, an existing SNP database on the same SLE cohort will be used to examine potential SNP associations with altered histone modifications. SNP analysis on RNA-Seq and ChIP- Seq data will allow allele-specific quantitation on controls, as a foundation for the SLE samples. This proposal will examine the epigenome in SLE and begin to examine potential causes and consequences. Collectively, these approaches will further our understanding of SLE and may develop a new paradigm for the understanding of the chronicity of autoimmune disease in general.

描述(申请人提供)：系统性红斑狼疮(SLE)是一种慢性系统性自身免疫性疾病。非洲裔美国女性受到的影响不成比例，病因被认为是遗传和环境因素共同作用的结果。自然病史通常包括不同的器官系统参与和一个被耀斑打断的慢性病程。多项研究表明，单核细胞功能在SLE中是异常的，这一点很重要，因为单核细胞可以作为分化的巨噬细胞持续存在于组织中，并形成适应性反应，从而由于其异常功能而产生一系列效应。巨噬细胞是动脉粥样硬化性疾病的初始病变，与系统性红斑狼疮的主要死亡原因有关，而巨噬细胞向肾脏的渗透与发病率和死亡率的增加特别相关。这些构成了研究SLE单核细胞的理论基础。我们特别假设，SLE疾病过程驱动单核细胞表观基因组的改变，这有助于疾病的永久存在和最终的器官表现。表达潜力的改变可能导致单核细胞的异常迁移或炎性介质的表达。对常见无害刺激的病理反应，如病毒，可能是表观基因组改变的结果。这项建议将研究SLE单核细胞的表观遗传学图景，并开始识别与组蛋白修饰改变相关的途径。两个相反的组蛋白标记将被CHIP-Seq、H3K4me2和H3K27me3检测。我们有初步数据表明，与对照组相比，SLE患者单核细胞中H4乙酰化水平发生了变化。对改变了组蛋白修饰的基因集进行的网络分析显示了具有生物学相关性的结节，包括已知的炎症途径。第二个表观遗传学特征，非编码RNA，将在探索性的基础上进行研究。初步数据显示，TNF1基因上游有组织特异性的反义RNA，与转录抑制物的结合有关。我们将研究长的类似mRNA的非编码RNA，并使用一种新的芯片序列方法，使用S9.6来探索潜在的调控RNA的结构。S9.6抗体将被用来鉴定DNA：RNA杂交结构，这将被用来过滤通过生物信息鉴定的非编码RNA。这项应用的主要目标之一是开始过渡到对表观基因组的改变进行机械性检查。我们假设疾病本身驱动了表观基因组的大部分改变，然而，同一SLE队列中现有的SNP数据库将被用于检查潜在的SNP与改变的组蛋白修饰的关联。对RNA-Seq和ChIP-Seq数据的SNP分析将允许对对照进行等位基因特异性定量，作为SLE样本的基础。这项建议将检查SLE的表观基因组，并开始检查潜在的原因和后果。总而言之，这些方法将加深我们对SLE的理解，并可能为理解自身免疫性疾病的慢性性开发一种新的范式。

项目成果

Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus.

系统性红斑狼疮中整合素极晚期抗原 4 的异常调节。

• DOI: 10.1177/0961203313475691
• 发表时间: 2013
• 期刊: Lupus
• 影响因子: 2.6
• 作者: Rahimi,H;Maurer,K;Song,L;Akhter,E;Petri,M;Sullivan,KE
• 通讯作者: Sullivan,KE

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies.

• DOI: 10.1007/s10875-017-0426-2
• 发表时间: 2017-10
• 期刊: Journal of clinical immunology
• 影响因子: 9.1
• 作者: Sullivan KE;Bassiri H;Bousfiha AA;Costa-Carvalho BT;Freeman AF;Hagin D;Lau YL;Lionakis MS;Moreira I;Pinto JA;de Moraes-Pinto MI;Rawat A;Reda SM;Reyes SOL;Seppänen M;Tang MLK
• 通讯作者: Tang MLK

Cytokine-induced monocyte characteristics in SLE.

• DOI: 10.1155/2010/507475
• 发表时间: 2010
• 期刊: Journal of biomedicine & biotechnology
• 作者: Zhang Z;Maurer K;Perin JC;Song L;Sullivan KE
• 通讯作者: Sullivan KE

The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs.

• DOI: 10.1371/journal.pone.0093846
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shi L;Zhang Z;Yu AM;Wang W;Wei Z;Akhter E;Maurer K;Costa Reis P;Song L;Petri M;Sullivan KE
• 通讯作者: Sullivan KE

SERPINB2 is regulated by dynamic interactions with pause-release proteins and enhancer RNAs.

• DOI: 10.1016/j.molimm.2017.05.005
• 发表时间: 2017-08
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Shii L;Song L;Maurer K;Zhang Z;Sullivan KE
• 通讯作者: Sullivan KE