Knowledge about the 3-D organization of the genome will offer great insights into how cells retrieve and process the genetic information. Knowing the spatial probability distributions of individual genes will provide deep insights into gene regulatory and replication processes, and fill in the missing links between epigenomics, functional genomics and structural biology. Differences in genome organization between disease and normal cells, or between cells at different developmental stages (e.g. stems cells and mature cells) can inspire the design of novel therapeutic interventions.
We are part of the NIH 4D Nucleome initiative and were awarded the Center for Mapping the 3D Genome Landscape.
We have been developing novel computational methods to determine 3D genome structures and establish a structure-function map of the genome. To address the challenge of modeling highly variable genome structures, we propose a novel population-based modeling approach, where we construct a large population of 3D genome structures that together are entirely consistent with all available experimental data, such as Hi-C, TCC and imaging experiments. We interpret the result in terms of probabilities of a sample drawn from a population of heterogeneous structures.
The 3D distribution of all proteins and assemblies in a cell is potent and versatile information. In addition to giving the quantity of complexes, such maps can reveal interactions and functional relationships through the statistical analysis of co-occurrence patterns. Cryo-electron tomography (cryo-ET) is able to provide 3D snapshots of cells under close-to-live conditions. However, retrieving the shapes and distribution of complexes is not trivial as a tomogram typically has low signal-to-noise ratio, missing data, and non-isotropic resolution. Furthermore, individual macromolecules are difficult to recognize in highly crowded environments. For the small proportion of protein complexes whose structures are known, methods have been developed to localize them in a cryo-ET map. An imminent important task is to discover and locate yet unknown complexes in cryo-ET maps