Genetic determinants of chromatin accessibility in T cell activation across human individuals [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86887 | GEO | 2018/07/12
REPOSITORIES: GEO
Similar Datasets
Project description:We analyzed 105 chromatin accessibility (ATAC-seq) profiles in activated primary CD4+ T cells from healthy donors to identify genetic variants associated with variability in chromatin accessibility (ATAC-QTLs).
2018-07-12 | GSE86886 | GEO
Project description:Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed Assay for Transposase-Accessible Chromatin (ATAC-seq) and RNA-seq profiles from activated primary CD4 + T cells of up to 105 healthy donors. We found that regions of chromatin accessibility (ATAC-peaks) are co-accessible at kilobase and megabase scales, in patterns consistent with the 3D organization of chromosomes measured by in situ Hi-C in T cells. Genetic variants located within ATAC-peaks often affected the accessibility of the corresponding peak and any co-accessible peaks. They also disrupt binding sites for transcription factors important for CD4 + T cell differentiation and activation, overlap and mediate expression QTLs from the same cells, and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression in primary immune cells that play a key role in many human diseases.
2018-07-01 | GSE115980 | GEO
Project description:<p>Profiling of gene expression with microarrays holds great potential for human health, for illuminating disease pathways or providing biomarkers to monitor disease or its resolution. Using high-throughput approaches for genotyping, immunophenotyping and gene expression analysis, the project will examine the basis for the control of gene expression in human immune cells, and how it is influenced by natural genetic variation or aging. In practice, the project will combine several cross-informative approaches: 1) Building on the established sample/data pipelines and robust protocols of the Immunological Genome (ImmGen) project, and on established cohorts of ethnically diverse healthy volunteers at hand, microarray techniques will be used to generate whole-genome expression profiles from purified naive CD4+ lymphocytes and monocytes from 600 healthy volunteers. A dense genetic map will be established for all donors. The results will elucidate how variation in the human genome affects the expression of immune genes, of key importance in understanding gene variants that bring susceptibility to immune or inflammatory disease. Computational analysis of these rich data will allow the reconstruction of regulatory connections between genes, helping to establish general modules and those specific of a given immune cell type. These data will be complemented by an orthogonal data group, generated from a restricted subset of 10 individuals, in which we will profile a larger set of 28 carefully delineated cell populations that exist in human blood. This work will also benefit from powerful interspecies comparison with similar experiments being performed in mice by ImmGen. 2) In addition, RNA from the same set of 28 defined cell populations will be probed with microarrays that explore other aspects of the transcriptome: i) microRNAs and other non-coding RNAs; ii) exon or splice junction arrays that will establish a map of differential splicing in human blood leukocyte. 3) The composition and reactivity of blood cells from the same donors will be established at the time of sample collection using high-throughput flow cytometry, correlating immune phenotypes with gene expression and genetic variation. 4) Genetic variability conditions the baseline levels of gene expression, but also the responsiveness to activating challenges. With samples from the same donors, NanoString technology for transcript counting will be used to analyze the transcriptional response of defined gene sets, representing response signatures of T or dendritic cells, for a fine-grained dissection of responses to different triggers (different bacterial ligands for dendritic cells, different cytokine environment for T cells). In keeping with the resource aspect of this project, all data and interpretations will be made publicly available rapidly upon curation, allowing public querying and browsing of the data, by using and evolving the existing web architectures of the ImmGen project, of the Broad Institute, and of international repositories. RELEVANCE: Exploration with DNA chips of the genome's expression microarrays holds great potential for human health, to better understand disease and to serve as diagnostic tools. Using a combination of high-throughput genomic techniques and computational biology, we will perform a broad exploration of gene expression in human blood cells across groups of African-American, Asian and European ancestry, asking how these profiles are affected by genetic variation or by age. These results will provide an invaluable reference benchmark for the interpretation of genetic and immunological studies.</p> <p>Additionally, over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, in a second study we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution. 15% of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (ATAC-QTLs). ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression, and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression.</p>
| phs000815 | dbGaP
Project description:We surveyed the variation and dynamics of active regulatory elements genome-wide in CD4+ T cells, using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) in longitudinal samples from healthy volunteers and during T cell activation. We created robust pipelines that enable accurate single molecule counting and allelic discrimination from clinical material. Over 4000 regulatory elements (7.2%) showed reproducible personal variation in activity. Gender was the most significant attributable source of regulome variation. ATAC-seq revealed novel elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately impact genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide foundational reference to compare disease-associated regulomes. We examined chromatin structure using ATAC-seq in purified human CD4+ T cells in 33 samples from 12 healthy donors and 15 samples from 3 patients with cutaneous T cell leukemia (CTCL). For T cell activation (TCA) time course, CD4+ cells from healthy donor 1 isolated as above were stimulated with ionomycin (1 ug/mL) and Phorbol Myristate Acetate (PMA; 20 ng/mL) and collected at 0, 1, 2, 4 hours in duplicate.
2015-06-23 | E-GEOD-60682 | biostudies-arrayexpress
Project description:ATAC-seq analysis of CD4 T cell populations obtained in blood of systemic lupus erythematosus (SLE) patients. The overall goal of this study was to determine chromatin accessibility profiles in Tfh cells and CXCR3+ PD1hi CD4+ T cells obtained from blood of SLE donors.
2018-02-02 | GSE110017 | GEO
Project description:To test the chromatin accessibility of different immune cell subsets, we isolated CD4+T cells, CD8+T cells, CD19+B cells and CD14+ monocytes from human PBMCs and performed ATAC assay.
2020-11-05 | E-MTAB-8982 | biostudies-arrayexpress
Project description:Coronary artery disease (CAD) is a complex inflammatory disease of the vessel wall and often leads to myocardial infarction. Genome-wide association studies (GWAS) have now identified over 200 genetic loci associated with CAD. The majority of CAD-associated variants are located in noncoding regions of the genome, many of which are predicted to regulate chromatin accessibility and gene expression. In this study, we performed ATAC-seq in human coronary artery patient samples to identify novel chromatin accessibility QTLs (caQTLs) and gain additional insights into CAD regulatory mechanisms in vivo.
2022-01-24 | GSE188422 | GEO
Project description:Atopic dermatitis (AD), the start of the atopic march, is one of the most common skin disorders in children. Immunologically, AD involves skin barrier defects and CD4+ T cells that localize to the skin, producing inflammatory cytokines and amplifying epidermal dysfunction. To understand the gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched healthy, non-allergic controls. Chromatin accessibility in stimulated CD4+ T cells were highly enriched for AD genetic risk variants. The vast majority of ATAC-seq peaks were shared, consistent with those sections of chromatin being equally available between matched pairs; however, NFKB DNA binding motifs were enriched in chromatin accessible in an AD-dependent manner. NFKB1 ChIP-seq identified peaks that were stronger in AD cases, enriched in controls, or shared between cases and controls. The ChIP-seq peaks that were statistically stronger in AD were more strongly enriched for NFKB DNA binding motifs. Chromatin that was more strongly accessibe and bound by NFKB1 in AD were enriched for genetic variants that increase risk for AD. Using whole genome sequencing data, we identified wide-spread genotype-dependent chromatin accessibility and allelic NFKB1 binding at AD and allergic disease genetic risk loci.
2022-04-26 | GSE189143 | GEO
Project description:Atopic dermatitis (AD), the start of the atopic march, is one of the most common skin disorders in children. Immunologically, AD involves skin barrier defects and CD4+ T cells that localize to the skin, producing inflammatory cytokines and amplifying epidermal dysfunction. To understand the gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched healthy, non-allergic controls. Chromatin accessibility in stimulated CD4+ T cells were highly enriched for AD genetic risk variants. The vast majority of ATAC-seq peaks were shared, consistent with those sections of chromatin being equally available between matched pairs; however, NFKB DNA binding motifs were enriched in chromatin accessible in an AD-dependent manner. NFKB1 ChIP-seq identified peaks that were stronger in AD cases, enriched in controls, or shared between cases and controls. The ChIP-seq peaks that were statistically stronger in AD were more strongly enriched for NFKB DNA binding motifs. Chromatin that was more strongly accessibe and bound by NFKB1 in AD were enriched for genetic variants that increase risk for AD. Using whole genome sequencing data, we identified wide-spread genotype-dependent chromatin accessibility and allelic NFKB1 binding at AD and allergic disease genetic risk loci.
2022-04-26 | GSE184301 | GEO
Project description:Atopic dermatitis (AD), the start of the atopic march, is one of the most common skin disorders in children. Immunologically, AD involves skin barrier defects and CD4+ T cells that localize to the skin, producing inflammatory cytokines and amplifying epidermal dysfunction. To understand the gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched healthy, non-allergic controls. Chromatin accessibility in stimulated CD4+ T cells were highly enriched for AD genetic risk variants. The vast majority of ATAC-seq peaks were shared, consistent with those sections of chromatin being equally available between matched pairs; however, NFKB DNA binding motifs were enriched in chromatin accessible in an AD-dependent manner. NFKB1 ChIP-seq identified peaks that were stronger in AD cases, enriched in controls, or shared between cases and controls. The ChIP-seq peaks that were statistically stronger in AD were more strongly enriched for NFKB DNA binding motifs. Chromatin that was more strongly accessibe and bound by NFKB1 in AD were enriched for genetic variants that increase risk for AD. Using whole genome sequencing data, we identified wide-spread genotype-dependent chromatin accessibility and allelic NFKB1 binding at AD and allergic disease genetic risk loci.
2022-04-26 | GSE184237 | GEO