Systematic mapping and prediction of gene-enhancer connections

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PROJECT SUMMARY The training program described in this supplement aims to bring diversity to NIH’s scientific workforce by supporting an underrepresented minority (URM) undergraduate student in an independent research experience to identify new mechanisms of disease risk in the human population. A fundamental challenge in modern biology is to identify the noncoding regulatory elements (REs) that control gene expression, which could inform the interpretation of the thousands of noncoding genetic variants associated with human diseases through genome-wide association studies (GWAS). Interpreting the functions of REs and noncoding genetic variants has been challenging because we have lacked the ability to systematically perturb REs in their native locations in the genome. To address this challenge, we recently developed a high-throughput method to map the functions of thousands of REs in their native genomic contexts and measure their quantitative effects on gene expression (CRISPRi tiling). We also developed a novel analytical approach to model and predict gene-RE connections based on maps of chromatin state and 3D folding. Together, these advances motivate a strategy to allow systematic mapping of all of the REs that control any given gene in any given cell type. The parent proposal aims to apply these tools to characterize the network architecture of gene-RE connections across hundreds of cell types, and edit single-nucleotide variants identified by the model in cellular models to characterize their effects on gene expression. These aims will provide insights into the mechanisms and architecture of gene-RE connectivity, generate tools for mapping gene-RE connectivity in any cell type, and reveal mechanisms underlying common diseases. The project supplement described here will use this project as a platform to provide a personalized training and mentorship program for a URM student involving an independent project at the interface of computational and experimental genomics; one-on-one mentorship on science, writing, and career development; and collaborative interactions with a broader scientific team in the Engreitz Laboratory in the Department of Genetics at Stanford University. Together, this training program will catapult a URM student to the forefront of genomics research to identify new mechanisms of disease risk in the human population.