Walking along chromosomes with super-resolution imaging, contact maps, and integrative modelling

Using the super-resolution microscopy methods of OligoSTORM and OligoDNA-PAINT, we trace 8 megabases of human chromosome 19, visualizing structures ranging in size from a few kilobases to over a megabase. Focusing on chromosomal regions that contribute to compartments identified with chromosome conformation capture, with our imaging we discover distinct structures that, in spite of considerable variability, can predict whether such regions correspond to active (A-type) or inactive (B-type) compartments. Imaging through the depths of an entire nuclei, we capture pairs of homologous regions in diploid cells, obtaining evidence that maternal and paternal homologous regions can be differentially organized. Finally, using restraint-based modeling to integrate imaging and Hi-C data, we implement a method – integrative modeling of genomic regions (IMGR) – to increase the genomic resolution of our traces to 10 kb. Grant: 1DP2OD008540: Exploring how the genome folds through proximity ligation and sequencing Grant: 4DP2OD008540: Exploring how the genome folds through proximity ligation and sequencing Grant: U01HL130010: Beyond Pairwise DNA Contacts: Exploring Higher-order Genome Structure Using Proximity Ligation NIH/4D Nucleome Consortium Grant: UM1HG009375: Genome-wide mapping of loops using in situ Hi-C Hi-C maps of 10 library replicates and a mega map