Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation

• Published in: eLife Vol. 13
• Main Authors: Pahl, Matthew C, Sharma, Prabhat, Thomas, Rajan M, Thompson, Zachary, Mount, Zachary, Pippin, James A, Morawski, Peter A, Sun, Peng, Su, Chun, Campbell, Daniel, Grant, Struan F A, Wells, Andrew D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 20.09.2024; eLife Sciences Publications, Ltd
• Subjects: Animals; Antigens; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmunity - genetics; CD28 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cell cycle; Cell proliferation; Chromatin; Chromatin - genetics; Chromatin - metabolism; Chromosomes and Gene Expression; Cytokines; DNA repair; Enhancer Elements, Genetic - genetics; Enhancers; Epigenetics; Gene expression; Gene Expression Regulation; Gene mapping; gene regulation; Genetic diversity; genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humans; immunology; Immunology and Inflammation; Interleukin 2; Interleukin-2 - genetics; Interleukin-2 - metabolism; Kinases; Lymphocyte Activation - genetics; Lymphocytes; Lymphocytes T; Metabolism; Mice; Molecular modelling; Pathogenesis; Principal components analysis; Regulatory sequences; Reproducibility; T cell receptors; Transcription activation; mouse; genetics; gene regulation; inflammation; chromosomes; human; immunology; epigenetics; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.96852

Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact -regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter-cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.