Project Summary Enhancers are fundamental gene regulatory elements with critical roles in development and disease, and yet relatively little is known about how enhancers themselves are regulated. What are the upstream gene pathways important for activating enhancers? Which proteins bind to an enhancer and modulate proximal gene expression? How do these regulatory factors affect complex phenotypes? While large-scale efforts such as the Encyclopedia of DNA Elements (ENCODE) Consortium have made laudable progress towards a compendium of enhancers, we lack the tools necessary to understand enhancer regulation, and more broadly, its role in disease. To address this critical shortcoming, I will first develop a new, high-throughput method — a trans massively parallel reporter assay or transMPRA — that can address current limitations of identifying protein-regulatory element interactions in a scalable manner. I will then apply transMPRA, along with other high-throughput genomics assays and multimodal data analysis, to reveal the comprehensive gene-regulatory basis of autoimmunity. I anticipate that this new method together with findings from its initial application will have broad implications toward understanding the role of gene regulation in complex traits including human autoimmune disorders. In addition to my research proposal, I will undergo a fellowship training plan that continues to refine my skills as a researcher and active contributor to the science community. The proposed research and fellowship training plan will take place in the labs of my sponsor and co-sponsor, Dr. Jay Shendure and Dr. Cole Trapnell, in the Department of Genome Sciences at University of Washington. I specifically chose my advisors and institution because they have an outstanding track record of performing cutting edge research and training the next generation of science thought leaders.