Coordination Funds

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Eukaryotic genomes encode the information that defines both general and specific characteristics of each cell type. However, the linear DNA sequence alone often fails to predict cellular functions and phenotypic outcomes. In fact, genomic information is modified and regulated by a number of additional layers of gene expression control. One of these, the spatial folding of chromosomes, has been recently identified as a critical such layer. Spatial chromosomal folding is established through binding of transcription factors as well as via epigenetic mechanisms and biophysical forces that act in a concerted manner to regulate gene expression in space and time. Therefore, studying the principles of three-dimensional chromatin folding allow us to unravel its contribution in gene regulation during development and disease. The primary goal of this Priority Program is to dissect the structure-to-function relationship of the genomes of higher metazoans at high spatiotemporal resolution in study systems relevant to genome integrity, development, and disease. Aside from the apparent goal of bringing together a critical mass of German-academia groups engaged in this line of research, we also aspire to host projects in this SPP that undertake in vitro and in vivo functional and mechanistic studies on model organisms and human samples that can deepen our understanding of how genome architecture underlies cell and tissue physiology. All projects (collaborative or standalone) should have a clear and substantial focus on mechanisms and forces driving or maintaining 3D chromatin folding and its role in gene regulation. A combination of advanced molecular methods, super‐resolution and/ or live‐cell imaging, precision genetic editing, and novel computational tools is envisaged. Thus, projects included in this 2nd SPP funding period should: (i) develop and apply novel technologies that can capture spatial chromatin conformation, also in conjunction with other genomic features (e.g., transcription, histone modifications, DNA methylation), to resolve and track features of genomic architecture in the nucleus down to the single cell-level; (ii) dissect the functional impact of 3D chromatin folding on gene expression or genome integrity in vitro and in vivo during development or cell differentiation; (iii) causally connect 3D chromatin folding with disease etiology via precision genome editing and patient data and/or disease models; (iv) develop and apply novel computational approaches allowing us to integrate, quantitatively model, and visualize the end-effects and dynamics of spatial genome organization. In the end, we aspire that the consortium will generate new knowledge bringing us closer to defining a parsimonious set of rules that explain the structure-to-function relationship of eukaryotic chromosomes.