Coordination Project for the Priority Programme "Spatial Genome Architecture in Development and Disease

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Already from the first complete draft of the human genome, it became apparent that the linear genetic information would not suffice to fully explain its many genomic functions and their complex regulation. What differentiates the identity and functions of individual cells and tissues is not their genomic content, but the regulation of each of their ~ 20,000 genes. Gene regulation is critically dependent on proximal and distal regulatory elements that act via chromatin looping to ensure physical proximity with their target promoters. The resulting spatial (3D) organization of chromosomes in the nucleus is now understood to have profound effects on gene regulation and transcriptional output. To exploit this emerging field of 3D genomics, The SPP will have the following major aims: (1) develop and apply novel and existing technologies to address the long-standing question of how chromosome conformation is regulated; (2) functionally dissect the impact of 3D chromatin folding on in in vitro and in vivo models during cell stimulation, differentiation or development; (3) investigate the role of 3D chromatin folding in disease pathology to understand this under-appreciated disease mechanism; (4) develop and apply novel computational tools and models to predict how 3D genome folding dynamics translate into changes in genomic output; (5) bring together an interdisciplinary group of scientists to advance and consolidate this emerging topic within the German research community.By focusing on chromatin folding and gene regulation, this SPP addresses a field of biomedicine that goes far beyond the study of genes and their function, to fully understand their regulation. Building on one of the most important discoveries in Genomics in the past decade, we take the next step in investigating how chromatin folding governs differentiation, development and disease, thereby addressing a pertinent question in Life Sciences: how cellular individuality is achieved at a genomic level. Once deciphered, these rules will allow us to predict how different cells respond to signaling cues upon development or disease manifestation.