Understanding human autoimmunity risk within the IL2RA super enhancer

Human disease risk has been linked to hundreds of variants in our DNA. Understanding of these unbiased genetic associations has long held the promise of revealing insights into disease mechanisms. However, disease-risk variants overwhelmingly reside in non-coding sequences – long stretches of our chromosomes that we still know relatively little about. Here I develop new tools and methodologies to understand genetic risk for disease for a critical autoimmunity locus, IL2RA. I first demonstrate that CRISPR activation can be adapted for high throughput enhancer screens. By tiling CRISPR-activation across the super-enhancer within the IL2RA locus, I systematically map functional IL2RA enhancers in the disease-associated non-coding sequences. Undertaking a genetic perturbation approach, I dissect how distinct IL2RA enhancers regulate immune cell function as well as shape risk of autoimmunity in vivo. Using CRISPR-engineered enhancer deletion mice and human immune cells I identified two novel IL2RA enhancers; a maintenance enhancer that controls IL2RA expression in anti-inflammatory regulatory T cells and a disease-associated IL2RA enhancer that controls the timing of IL2RA induction in pro-inflammatory immune cells. Having discovered enhancers that regulate IL2RA in different contexts I interrogated their effects in an in vivo model of autoimmune disease. Deletion of the conserved stimulation-responsive enhancer that harbors a human variant protective against T1D completely protected non-obese diabetic (NOD) mice from diabetes. This work decodes a critical autoimmunity association, develops a cis-regulatory framework at the IL2RA locus, and causally links IL2RA gene regulation to autoimmunity. The tools and strategies developed in these studies can be used to decode disease-associated loci in the human genome