Disease and Race Specific Single-cell Epigenetic Mechanisms in Human SLE

人类 SLE 的疾病和种族特异性单细胞表观遗传机制

• 批准号: 10612368
• 负责人: Patrick M Gaffney
• 金额: $ 85.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612368
• 关键词: ATAC-seq; African American; Age; Alleles; Allelic Imbalance; American; Antigens; Architecture; Autoantigens; Autoimmune Diseases; Automobile Driving; Biological Assay; Cells; Cerebritis; Chromatin; Classification; Clinical; Clinical Data; Collaborations; Control Groups; Cryopreservation; Data; Diagnosis; Disease; Disparity; Disparity in diagnosis; Doctor of Philosophy; Epigenetic Process; European; Exhibits; Family-Based Registry; Feasibility Studies; Gene Expression; Genetic; Genetic Processes; Genetic Variation; Genetic study; Genome; Genomic Segment; Genotype; Goals; Histones; Human; Immune Tolerance; Inflammatory; Interferons; Investigation; Knowledge; Laboratories; Lupus; Methods; Molecular; Nephritis; Organ; Outcome; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Positioning Attribute; Process; Quantitative Trait Loci; Race; Regulatory Element; Reporter; Research; Resources; Risk; Role; Sampling; Self Tolerance; Shapes; Single Nucleotide Polymorphism; Systemic Lupus Erythematosus; Technology; Testing; Time; Transposase; Validation; Variant; case control; cell type; clinical phenotype; clinically actionable; data integration; disorder risk; epigenetic regulation; epigenome; experience; genetic architecture; genetic information; genome-wide; indexing; innovation; mortality; peripheral blood; population based; programs; prototype; racial difference; racial disparity; repository; response; risk variant; success; transcriptome; transcriptome sequencing; transcriptomics; translational genetics

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by dysregulated interferon responses and loss of self-tolerance to cellular antigens that result in inflammatory processes that ultimately lead to systemic end-organ damage. Striking genetic and clinical differences exist between European American (EA) and African American (AA) SLE patients that result in disparities in their diagnoses, management and outcomes. Despite decades of research and over 100 risk loci identified, the underlying mechanisms driving the pathogenesis of SLE and its racial disparities remain incompletely understood. Our lab has joined forces with the team led by Jason Buenrostro, PhD, at Harvard to evaluate and understand how epigenetic regulation in specific cell types contributes to both disease- and race-specific SLE pathogenesis. We use a sci-ATAC-seq (single cell indexing assay for transposase-accessible chromatin), method developed and optimized in the Buenrostro laboratory, to assess disease- and race-specific differences in genome-wide chromatin accessibility (CA) in cell subtypes from cryopreserved peripheral blood mononuclear cells. Integrating these data with genotyping data allows us to identify allelically imbalanced variants that are enriched in regions of CA (caQTLs), suggesting a mechanistic role for these variants in regulating CA. Our preliminary data conducted in EA SLE and healthy controls demonstrate that we are able to define multiple major PBMC cell subsets, and that extensive differential CA and caQTLs discriminate between SLE case and control subjects. We now propose an expanded study that will not only evaluate disease-specific CA and caQTL alterations in a much larger sample, but also race-specific alterations. Integrating single-cell transcriptomic data and clinical data with CA and caQTL data will facilitate the functional interpretation of SLE relevant CA differences. Our goals for this AR077434 resubmission are to 1) define cell type-specific differences in chromatin accessibility that identify both disease- specific and race-specific alterations; 2) identify cell type and race-specific caQTLs that associate with differences in CA between SLE cases and controls; and 3) define the mechanistic relationships between CA, caQTLs, gene expression architectures, within the context of cis co-accessibility networks. We believe this project positions us at the leading edge to develop a precise epigenetic roadmap connecting genetic variation to deleterious cellular and clinical phenotypes that underlie the disease-specific mechanisms of SLE and its remarkable race-specific disparities.

项目总结 系统性红斑狼疮(SLE)是一种以调节失调为特征的自身免疫性疾病 干扰素反应和对细胞抗原的自我耐受性丧失，导致炎症过程 最终导致全身性终末器官损伤。欧洲人在遗传和临床上存在显著差异 美国人(EA)和非裔美国人(AA)SLE患者在诊断、治疗方面存在差异 和结果。尽管经过几十年的研究和100多个风险位点的确定，潜在的驱动机制 系统性红斑狼疮的发病机制及其种族差异仍不完全清楚。我们的实验室已经联合了 哈佛大学Jason Buenrostro博士领导的团队评估和了解表观遗传调控是如何 特定的细胞类型对疾病和种族特异性SLE的发病都有贡献。我们使用SCI-ATAC-SEQ (转座酶可及染色质的单细胞指数法)，该方法在 Buenrostro实验室，以评估全基因组染色质可获得性中疾病和种族特异性差异 (Ca)从深低温保存的外周血单核细胞中分离出的细胞亚群。将这些数据与 基因分型数据使我们能够识别在CA(CaQTL)区域富含的等位不平衡变异， 这表明这些变体在调节CA方面起着机械性的作用。我们在EA SLE中进行的初步数据 和健康对照表明，我们能够定义多个主要的PBMC细胞亚群，并且广泛的 差异性CA和caQTL在SLE患者和对照组之间存在差异。我们现在提议扩展一个 这项研究不仅将在更大的样本中评估疾病特异性CA和caQTL的变化，而且还将 特定于种族的更改。将单细胞转录数据和临床数据与CA和caQTL数据集成 将有助于对SLE相关CA差异的功能解释。我们这款AR077434的目标 重新提交是1)确定染色质可及性中细胞类型的特定差异，以识别两种疾病- 特定和特定于种族的改变；2)识别与以下相关的细胞类型和特定于种族的caQTL SLE患者和对照组之间CA的差异；3)明确CA、 CaQTL，基因表达架构，在顺式可及性网络的背景下。我们相信这一点 该项目使我们处于领先地位，以开发一张精确的表观遗传路线图，将遗传变异与 恶性细胞和临床表型是系统性红斑狼疮及其致病机制的基础 明显的种族差异。

项目成果

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3.

• DOI: 10.3389/fgene.2022.1011965
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7

Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases.

大规模平行报告基因检测证实了 hQTL 的调控潜力，并揭示了狼疮和其他自身免疫性疾病的重要变异。

• DOI: 10.1101/2023.08.17.553722
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Fu,Yao;Kelly,JenniferA;Gopalakrishnan,Jaanam;Pelikan,RichardC;Tessneer,KandiceL;Pasula,Satish;Grundahl,Kiely;Murphy,DavidA;Gaffney,PatrickM
• 通讯作者: Gaffney,PatrickM