Chromatin conformation dynamics during CD4+ T cell activation implicates autoimmune disease-associated genes and regulatory elements

Abstract Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with autoimmune disease, but the causal variants and their contribution to immune dysregulation remain largely unknown. We measured the dynamics of chromosome conformation, chromatin accessibility, and gene transcription across three phases of naive human CD4+ T cell activation and co-localized active cis-regulatory elements with the 95% credible set of variants from 15 autoimmune GWAS. Reorganization of chromosome structure placed these elements in direct contact with ~1,200 protein-coding genes, at least one-third of which were dynamically regulated by stimulation. The set of implicated genes is enriched for high-throughput CRISPR screen targets that control multiple aspects of CD4+ T cell activation, and we pharmacologically validated eight novel gene products as potent regulators of T cell proliferation. These maps also allowed the identification and functional validation of a novel stretch of intergenic enhancers whose activity is required for IL2 gene expression and is influenced by autoimmune-associated genetic variation. This study represents a powerful strategy and resource for assigning physiologic relevance to autoimmune-risk variants and identifying novel genes that control T cell activation and function.