An integrated 3-dimensional genome modeling engine for data-driven simulation of spatial genome organization
ChIA-PET is a high-throughput mapping technology that reveals long-range chromatin interactions and provides insights into the basic principles of spatial genome organization and gene regulation mediated by specific protein factors. Recently, we showed that a single ChIA-PET experiment provides information at all genomic scales of interest, from the high-resolution locations of binding sites and enriched chromatin interactions mediated by specific protein factors, to the low resolution of nonenriched interactions that reflect topological neighborhoods of higher-order chromosome folding. This multilevel nature of ChIA-PET data offers an opportunity to use multiscale 3D models to study structural-functional relationships at multiple length scales, but doing so requires a structural modeling platform. Here, we report the development of 3D-GNOME (3-Dimensional Genome Modeling Engine), a complete computational pipeline for 3D simulation using ChIA-PET data. 3D-GNOME consists of three integrated components: a graph-distance-based heat map normalization tool, a 3D modeling platform, and an interactive 3D visualization tool. Using ChIA-PET and Hi-C data derived from human B-lymphocytes, we demonstrate the effectiveness of 3D-GNOME in building 3D genome models at multiple levels, including the entire genome, individual chromosomes, and specific segments at megabase (Mb) and kilobase (kb) resolutions of single average and ensemble structures. Further incorporation of CTCF-motif orientation and high-resolution looping patterns in 3D simulation provided additional reliability of potential biologically plausible topological structures. ; D.P., P.S., M.S., and M.J.P. are supported by grants from the Polish National Science Centre (2014/15/B/ST6/05082 and 2013/09/B/ NZ2/00121), and the European Cooperation in Science and Technology action (COST BM1405 and BM1408). P.S. and D.P. are supported by funds from National Leading Research Centre in Bialystok and the European Union under the European Social Fund. Y.R. is supported by the Director Innovation Fund from the Jackson Laboratory and National Cancer Institute (NCI) grant R01 CA186714. Y.R. is also supported by the Roux family as a Florine Roux Endowed Chair and Professor in Genomics and Computational Biology. All authors were supported by National Institutes of Health grant 1U54DK107967-01, "Nucleome Positioning System for Spatiotemporal Genome Organization and Regulation," within the 4DNucleome NIH program.