TY - JOUR T1 - Discovery of an autoimmunity-associated <em>IL2RA</em> enhancer by unbiased targeting of transcriptional activation JF - bioRxiv DO - 10.1101/091843 SP - 091843 AU - Dimitre R. Simeonov AU - Benjamin G. Gowen AU - Mandy Boontanrart AU - Theodore Roth AU - Youjin Lee AU - Alice Chan AU - Michelle L. Nguyen AU - Rachel E. Gate AU - Meena Subramaniam AU - Jonathan M. Woo AU - Therese Mitros AU - Graham J. Ray AU - Nicolas L. Bray AU - Gemma L. Curie AU - Nicki Naddaf AU - Eric Boyer AU - Frederic Van Gool AU - Kathrin Schumann AU - Mark J. Daly AU - Kyle K. Fahr AU - Chun Ye AU - Jeffrey A. Bluestone AU - Mark S. Anderson AU - Jacob E. Corn AU - Alexander Marson Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/12/05/091843.abstract N2 - The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell type-specific transcriptional programs and responses to specific extracellular cues 1-3. In order to understand the mechanisms by which non-coding genetic variation contributes to disease, systematic mapping of functional enhancers and their biological contexts is required. Here, we develop an unbiased discovery platform that can identify enhancers for a target gene without prior knowledge of their native functional context. We used tiled CRISPR activation (CRISPRa) to synthetically recruit transcription factors to sites across large genomic regions (&gt;100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA (interleukin-2 receptor alpha; CD25). We identified several CRISPRa responsive elements (CaREs) with stimulation-dependent enhancer activity, including an IL2RA enhancer that harbors an autoimmunity risk variant. Using engineered mouse models and genome editing of human primary T cells, we found that sequence perturbation of the disease-associated IL2RA enhancer does not block IL2RA expression, but rather delays the timing of gene activation in response to specific extracellular signals. This work develops an approach to rapidly identify functional enhancers within non-coding regions, decodes a key human autoimmunity association, and suggests a general mechanism by which genetic variation can cause immune dysfunction. ER -