3D genome organization and modifications are fundamental to cellular functions. Genomic DNAs, typically 2 million base pairs long and organized into chromosomes, are compacted within a cell nucleus measuring 10-20 μm in diameter. Proper folding is crucial for maintaining nuclear organization and facilitating essential cellular processes such as gene expression regulation and cellular specialization. 

To explore the relationship between genome 3D structure and function, the INCITE team will pursue a large-scale computational campaign aimed at constructing detailed 3D models of genome folding across four distinct cell types. These models will enable the team to investigate the structural basis of genome folding and its functional implications providing comprehensive maps of how genes at various loci adopt distinct spatial configurations, influence cellular states, and modulate gene expression. Additionally, they will generate highly accurate, fine-resolution ensemble models of single-cell 3D chromatin conformations for all genomic loci and diploid genomes. Their analysis will delineate tissue-specific master regulatory interactions and conserved interactions across cell types. It will also characterize chromatin structural heterogeneity by identifying major structural clusters in cell subpopulations. Moreover, the researchers will develop a high-quality database of enhancer- gene target pairs and train a machine learning predictor to identify such pairs genome-wide across various cell types. This approach is crucial for understanding genome topology, gene expression, and discovering potential causal genes for noncoding risk variants identified in genome-wide association studies.