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      Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

      Science (New York, N.Y.)

      Biotin, Sequence Analysis, DNA, Protein Conformation, Principal Component Analysis, Nucleic Acid Conformation, Monte Carlo Method, Models, Molecular, In Situ Hybridization, Fluorescence, Humans, Genome, Human, Gene Library, chemistry, DNA, Computational Biology, ultrastructure, Chromosomes, Human, Chromatin Immunoprecipitation, Chromatin, Cell Nucleus, Cell Line, Transformed

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          Abstract

          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.

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          Most cited references 20

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          Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements.

          Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also identified a new looping interaction in K562 cells between the beta-globin Locus Control Region and the gamma-beta-globin intergenic region. Interestingly, this region has been implicated in the control of developmental globin gene switching. 5C should be widely applicable for large-scale mapping of cis- and trans- interaction networks of genomic elements and for the study of higher-order chromosome structure.
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            Active genes dynamically colocalize to shared sites of ongoing transcription.

            The intranuclear position of many genes has been correlated with their activity state, suggesting that migration to functional subcompartments may influence gene expression. Indeed, nascent RNA production and RNA polymerase II seem to be localized into discrete foci or 'transcription factories'. Current estimates from cultured cells indicate that multiple genes could occupy the same factory, although this has not yet been observed. Here we show that, during transcription in vivo, distal genes colocalize to the same transcription factory at high frequencies. Active genes are dynamically organized into shared nuclear subcompartments, and movement into or out of these factories results in activation or abatement of transcription. Thus, rather than recruiting and assembling transcription complexes, active genes migrate to preassembled transcription sites.
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              Nuclear organization of the genome and the potential for gene regulation.

              Much work has been published on the cis-regulatory elements that affect gene function locally, as well as on the biochemistry of the transcription factors and chromatin- and histone-modifying complexes that influence gene expression. However, surprisingly little information is available about how these components are organized within the three-dimensional space of the nucleus. Technological advances are now helping to identify the spatial relationships and interactions of genes and regulatory elements in the nucleus and are revealing an unexpectedly extensive network of communication within and between chromosomes. A crucial unresolved issue is the extent to which this organization affects gene function, rather than just reflecting it.
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                Author and article information

                Journal
                19815776
                2858594
                10.1126/science.1181369

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