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Cell. 2019 Mar 7;176(6):1502-1515.e10. doi: 10.1016/j.cell.2019.01.020. Epub 2019 Feb 21.

Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization.

Author information

1
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
2
High-throughput Imaging Facility, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
4
Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
5
Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.

Abstract

Several general principles of global 3D genome organization have recently been established, including non-random positioning of chromosomes and genes in the cell nucleus, distinct chromatin compartments, and topologically associating domains (TADs). However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are still poorly characterized. Here, we systematically probe heterogeneity in genome organization. High-throughput optical mapping of several hundred intra-chromosomal interactions in individual human fibroblasts demonstrates low association frequencies, which are determined by genomic distance, higher-order chromatin architecture, and chromatin environment. The structure of TADs is variable between individual cells, and inter-TAD associations are common. Furthermore, single-cell analysis reveals independent behavior of individual alleles in single nuclei. Our observations reveal extensive variability and heterogeneity in genome organization at the level of individual alleles and demonstrate the coexistence of a broad spectrum of genome configurations in a cell population.

PMID:
30799036
PMCID:
PMC6408223
[Available on 2020-03-07]
DOI:
10.1016/j.cell.2019.01.020

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