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

PLoS Genet. 2018 Dec 26;14(12):e1007872. doi: 10.1371/journal.pgen.1007872. eCollection 2018 Dec.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cells, Cultured
  • Chromosome Painting / methods
  • Chromosome Structures / chemistry
  • Chromosome Structures / genetics
  • Chromosome Structures / ultrastructure
  • Chromosome Walking / methods*
  • Chromosomes, Human, Pair 19 / chemistry
  • Chromosomes, Human, Pair 19 / genetics*
  • Chromosomes, Human, Pair 19 / ultrastructure*
  • Female
  • Fluorescent Dyes
  • Humans
  • Imaging, Three-Dimensional
  • In Situ Hybridization, Fluorescence / methods
  • Male
  • Models, Genetic*
  • Oligonucleotide Probes
  • Pedigree

Substances

  • Fluorescent Dyes
  • Oligonucleotide Probes