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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
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Journal Article
Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis
2020
Overview
Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including
FOXO1
, which we confirm using CRISPR/Cas9.
Although genome-wide association studies have identified genetic variation contributing to disease risk, assigning causal genes is challenging. Here, the authors generate ATAC-seq, Hi-C, Capture Hi-C and RNA-seq data in stimulated CD4+ T cells to identify functional enhancers and demonstrate interactions of expression quantitative trait loci with target genes in rheumatoid arthritis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/43
/ 38/77
/ 38/91
/ 42/109
/ Arthritis, Rheumatoid - genetics
/ Autoimmune Diseases - genetics
/ CD4-Positive T-Lymphocytes - cytology
/ CD4-Positive T-Lymphocytes - metabolism
/ CRISPR
/ DNA
/ Forkhead Box Protein O1 - genetics
/ Forkhead Box Protein O1 - metabolism
/ Genes
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ RNA
/ Science
