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how?
Tools we developed for mapping the spatial organization of genomes: 3C, 5C and Hi-C.
We developed Chromosome Conformation Capture (3C) that is used to detect physical interactions between genomic elements (Dekker et al. Science, 2002). Using 3C we, and others, discovered that gene regulation is mediated by the three-dimensional organization of chromosomes that brings genes and their regulatory elements in close spatial proximity. 3C is now widely used and already has had a major impact on studies of genome regulation.

Large-scale detection of long-range chromatin interactions will be instrumental in mapping genome-wide networks of communication between genomic elements and the determination of the three-dimensional folding of the genome. We were the first to combine 3C with ultra-high-throughput DNA sequencing, thereby dramatically increasing the scale at which interactions between genomic loci can be studied. Specifically, we have developed 5C, a high-throughput version of 3C for large-scale mapping of chromatin interaction networks (Dostie et al. Genome Res. 2006).

To enable the community to adopt 5C and related technologies we have developed 'my5C', a publicly available set of computational tools for design of 5C studies and for visualization and analysis of large chromatin interaction data sets (my5C.umassmed.edu; Lajoie et al. Nature Methods 2009).

Ultimately we aim to obtain detailed insights into the three-dimensional arrangements of complete genomes at Kb resolution. To this end we recently developed the Hi-C technology: a genome-wide and unbiased method that combines 3C with deep sequencing (Lieberman-Aiden, van Berkum et al. Science 2009). We have applied Hi-C to generate the first comprehensive and unbiased long-range interaction maps of the human genome. Hi-C data reveal both known hallmarks of nuclear organization (e.g. formation of chromosome territories, and preferred co-location of particular pairs of chromosomes) as well as novel folding principles of chromosomes. First, we found that the human genome is divided over two types of spatial compartments, one containing active chromatin, and one containing all inactive segments of the genome. Second, we discovered a novel higher order chromatin folding motif: at the megabase scale, our data are consistent with a model in which chromatin is described by a polymer state known as the fractal globule: a knot-free conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. This conformation is an extremely efficient solution for packing long chromosomes inside the nucleus. Hi-C data for GM06990 lymphoblastoid cells and for K562 erythroleukemia cells is available in user friendly format at our website: hic.umassmed.edu.