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

Abstract

Chromosome organization is crucial for genome function. Here, we present a method for visualizing chromosomal DNA at super-resolution and then integrating Hi-C data to produce three-dimensional models of chromosome organization. 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, 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 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.

This work was supported by funds from Ministerio de Ciencia, Innovación y Universidades of Spain (http://www.ciencia.gob.es/) (IJCI-2015-23352) to IF, Damon Runyon Cancer Research Foundation (https://www.damonrunyon.org/) and Howard Hughes Medical Institute (https://www.hhmi.org/) to BJB, Uehara Memorial Foundation Research (https://www.taisho-holdings.co.jp/en/environment/social/sciences/) to HMS, William Randolph Hearst Foundation (https://www.hearstfdn.org/) to RBM, EMBO (Long-Term fellowship) (https://www.embo.org/) to JE, NSF (Center for Theoretical Biological Physics, Rice University) (https://www.nsf.gov/) to MDP and JNO, NSF (CCF-1054898, CCF-1317291) (https://www.nsf.gov/), NIH (1R01EB018659-01, 1-U01- MH106011-01) (https://www.nih.gov/), and Office of Naval Research (N00014-13-1-0593, N00014-14-1-0610, N00014-16-1-2182, N00014-16-1- 2410) (https://www.onr.navy.mil/) to PY, NIH (1DP2OD008540, U01HL130010, UM1HG009375, 4DP2OD008540) (https://www.nih.gov/), NSF (PHY-1427654) (https://www.nsf.gov/), USDA (2017-05741) (https://www.usda.gov/), Welch Foundation (Q-1866) (http://www.welch1.org/), NVIDIA (https://www.nvidia.com/en-us/), IBM (https://www.ibm.com/us-en/?lnk=m), Google (https://www.google.com/), Cancer Prevention Research Institute of Texas (R1304) (http://www.cprit.state.tx.us/), and McNair Medical Institute (http://www.mcnairfoundation.org/what-we-fund/mcnair-medical-institute/) to E.L.A., Horizon 2020 Research and Innovation Programme (676556) (https://ec.europa.eu/programmes/horizon2020/en/), European Research Council (609989) (https://erc.europa.eu/), Ministerio de Ciencia, Innovación y Universidades of Spain (BFU2017-85926-P) (http://www.ciencia.gob.es/), CERCA, and AGAUR Programme of the Generalitat de Catalunya and Centros de Excelencia Severo Ochoa (SEV-2012-0208) (http://www.ciencia.gob.es/portal/site/MICINN/menuitem.7eeac5cd345b4f34f09dfd1001432ea0/?vgnextoid=cba733a6368c2310VgnVCM1000001d04140aRCRD) to M.A.M-R., and NIH (5DP1GM106412, R01HD091797, R01GM123289) (https://www.nih.gov/) to C-tW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.