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Science 9 October 2009:
Vol. 326. no. 5950, pp. 289 - 293
DOI: 10.1126/science.1181369
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Reports

Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome

Erez Lieberman-Aiden,1,2,3,4,* Nynke L. van Berkum,5,* Louise Williams,1 Maxim Imakaev,2 Tobias Ragoczy,6,7 Agnes Telling,6,7 Ido Amit,1 Bryan R. Lajoie,5 Peter J. Sabo,8 Michael O. Dorschner,8 Richard Sandstrom,8 Bradley Bernstein,1,9 M. A. Bender,10 Mark Groudine,6,7 Andreas Gnirke,1 John Stamatoyannopoulos,8 Leonid A. Mirny,2,11 Eric S. Lander,1,12,13,{dagger} Job Dekker5,{dagger}

We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

1 Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), MA 02139, USA.
2 Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.
3 Program for Evolutionary Dynamics, Department of Organismic and Evolutionary Biology, Department of Mathematics, Harvard University, Cambridge, MA 02138, USA.
4 Department of Applied Mathematics, Harvard University, Cambridge, MA 02138, USA.
5 Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6 Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
7 Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA.
8 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
9 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
10 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
11 Department of Physics, MIT, Cambridge, MA 02139, USA.
12 Department of Biology, MIT, Cambridge, MA 02139, USA.
13 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: lander{at}broadinstitute.org (E.S.L.); job.dekker{at}umassmed.edu (J.D.)

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