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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要全身性红斑狼疮（SLE）是一种原型自身免疫性疾病，其特征是失调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系统性的最终器官损坏。欧洲之间存在惊人的遗传和临床差异美国（EA）和非裔美国人（AA）SLE患者，导致诊断差异和结果。尽管进行了数十年的研究并确定了100多个风险基因座，但驱动的基本机制 SLE及其种族差异的发病机理仍未完全理解。我们的实验室已经与由哈佛大学Jason Buenrostro博士领导的团队，以评估和了解表观遗传调节特定的细胞类型有助于疾病和种族特异性的SLE发病机理。我们使用sci-atac-seq （转座酶可访问染色质的单细胞索引测定），在该方法中开发和优化 Buenrostro实验室，以评估全基因组染色质可及性的疾病和种族特异性差异（CA）在冷冻保存的外周血单核细胞中的细胞亚型中。将这些数据与基因分型数据使我们能够识别出富含CA（CAQTL），，，，，CAQTLS）的等位基因不平衡变体。提出这些变体在调节Ca中的机械作用。我们在EA SLE中进行的初步数据健康的对照表明，我们能够定义多个主要的PBMC细胞子集，并且很广泛差异CA和CAQTL区分SLE病例和控制受试者。我们现在建议扩展研究不仅会评估更大的样本中的疾病特异性CA和CAQTL改变，还可以评估特定种族的改变。将单细胞转录组数据和临床数据与CA和CAQTL数据集成将促进相关CA差异的功能解释。我们的AR077434目标重新提交为1）定义染色质可及性中细胞类型特异性差异，以识别这两种疾病 - 具体和特定种族的变化； 2）确定与之相关的细胞类型和种族特异性CAQTL SLE病例和对照之间的CA差异； 3）定义CA之间的机械关系 CAQTL，基因表达体系结构，在CIS的可及性网络的背景下。我们相信这一点项目将我们定位在前沿，以开发一个将遗传变异连接到的精确表观遗传路线图有害的细胞和临床表型是SLE及其疾病特异性机制的基础显着的种族特异性差异。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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
影响因子：
0
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