Th190 - Chromatin Conformation During CD4+ T Cell Activation Implicates Autoimmune Disease Candidate Genes

Matthew Pahl – The Children's Hospital of Philadelphia; Rajan Thomas – The Children's Hospital of Philadelphia; Zachary Mount – The Children's Hospital of Philadelphia; James Pippin – The Children's Hospital of Philadelphia; Struan Grant – The Children's Hospital of Philadelphia; Andrew Wells – The Children's Hospital of Philadelphia

Abstract Text: Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these genetic signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). As cRE function is dynamic across tissue types and cellular states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants act to contribute to disease risk. Here, we localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 costimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured gene expression, chromatin accessibility, and promoter-cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified 1,200 protein-coding genes physically connected to accessible disease-associated variants for 423 GWAS signals, at least one-third of which are dynamically regulated upon activation. From these maps, we functionally validated a novel stretch of intergenic enhancers whose activity is required for activation-induced IL2 gene expression and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes shown by high-throughput CRISPR screens to control CD4+ T cell proliferation and function, and we also pharmacologically validated 8 novel implicated genes as potent 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.