GRK 2403: Dissecting and Reengineering the Regulatory Genome

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The complex developmental processes that enable an organism to differentiate a multitude of cell types from one genome are encoded in the intricacies of gene regulation, not the availability of a large repertoire of genes. The completion of the human genome has enabled us to decipher the processes that control gene regulation, from its context in three-dimensional chromosome folding to how specific transcription factors act, and finally, to its product as RNA or protein. Unraveling the multiscale genetic regulatory code requires experimental methods that are increasingly able to query regulatory function at genome-wide and high-throughput levels. A wide range of readouts can now be obtained from single cells, from in vitro effects of individual DNA sites to the in vivo impact of whole regulatory regions. Mechanistic readouts can be derived from genome editing that enables us to alter genomic sequence and to use “epigenetic” modifications to perturb the activity of regulatory regions.The resulting data create a need for sophisticated computational approaches to interpret the results and gain insights into cellular regulatory processes. Machine learning methods have seen a quantum leap in their ability to automatically infer higher-level representations from large complex data, e.g. in the context of deep learning. Combining experimental and computational approaches will provide an unprecedented opportunity to teach the next generation of researchers a quantitative understanding of genome function and gene regulation within the context of biological systems. The proposed alliance between Berlin institutions, led by Humboldt University, and Duke University will address this challenge through an international research training group (IRTG) composed of three complementary areas. (1) High-throughput genomics and editing, (2) bioinformatics and machine learning, and (3) developmental systems biology.Doctoral researchers will obtain a significant amount of their training at the partner institution, thereby benefitting from the synergy and expertise at both sites. They will be co-advised by computational and biological experts from both sides of the Atlantic throughout their training. A customized program will support the students in bridging the three emphasis areas and acquiring critical skills to prepare them for future careers at the cutting edge of academia and industry. New graduate courses will be complemented by research opportunities for undergraduates. A focus on online materials and resources will promote an interconnected learning and research environment. Outreach efforts will engage the public in the discussion of opportunities and challenges of genome engineering and large-scale computation. Our students will become future leaders in the ongoing transformation of biology into a quantitative discipline, with a long-term impact on how genomics affects numerous aspects of human life.