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

• DOI: 10.7554/elife.96852.1
• Publication Date: 2024-05-13T16:25:44Z
• Authors: Matthew C. Pahl; Prabhat Sharma; Rajan M. Thomas; Zachary Thompson; Zachary Mount; James Pippin; Peter A. Morawski; Peng Sun; Chun Su; Daniel J. Campbell; Struan F.A. Grant; Andrew D. Wells
• Keywords: CD4-Positive T-Lymphocytes; epigenetics; QH301-705.5; Science; Q; R; Autoimmunity; Chromosomes and Gene Expression; Lymphocyte Activation; Chromatin; Autoimmune Diseases; immunology; Mice; Enhancer Elements, Genetic; Gene Expression Regulation; Medicine; Humans; Interleukin-2; Animals; genetics; Biology (General); gene regulation; Genome-Wide Association Study

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