Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, United States
Prabhat Sharma
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States
Rajan M Thomas
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States
Zachary Thompson
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States
Zachary Mount
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States
James A Pippin
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, United States
Peter A Morawski
Benaroya Research Institute at Virginia Mason, Seattle, United States
Peng Sun
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States
Chun Su
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, United States
Daniel Campbell
Benaroya Research Institute at Virginia Mason, Seattle, United States; Department of Immunology, University of Washington School of Medicine, Seattle, United States
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, United States
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States; Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
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 cis-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 IL2 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.