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

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

Author information

1
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
2
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
3
Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
4
Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.
5
Bruker Nano Inc., Salt Lake City, Utah, United States of America.
6
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America.
7
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
8
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
9
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America.
10
Department of Structural Biology, Stanford University School of Medicine, Stanford, California, United States of America.
11
Zero Epsilon, LLC, Salt Lake City, Utah, United States of America.
12
Bruker Nano Inc., Middleton, Wisconsin, United States of America.
13
Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, Texas, United States of America.
14
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona, Spain.
15
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
16
ICREA, Barcelona, Spain.

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.

PMID:
30586358
PMCID:
PMC6324821
DOI:
10.1371/journal.pgen.1007872
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: C-tW, BJB, RBM, SCN, SC, and HQN hold or have patent filings pertaining to Oligopaints and related technologies, including other oligo-based methods for imaging. These technologies may be licensed to ReadCoor, a company in which C-tW holds equity. PY and BJB have filed patents related to DNA-PAINT. DNA-PAINT technology has been licensed to Ultivue Inc., a company in which PY is an equity holder and cofounder. PY is also a co-founder of NuProbe Global.

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