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Nature Methods 3, 511–518 (1 July 2006) | doi:10.1038/nmeth890

Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays

Peter J Sabo , Michael S Kuehn , Robert Thurman , Brett E Johnson , Ericka M Johnson , Hua Cao , Man Yu , Elizabeth Rosenzweig , Jeff Goldy , Andrew Haydock , Molly Weaver , Anthony Shafer , Kristin Lee , Fidencio Neri , Richard Humbert , Michael A Singer , Todd A Richmond , Michael O Dorschner , Michael McArthur , Michael Hawrylycz , Roland D Green , Patrick A Navas , William S Noble & John A Stamatoyannopoulos

Localized accessibility of critical DNA sequences to the regulatory machinery is a key requirement for regulation of human genes. Here we describe a high-resolution, genome-scale approach for quantifying chromatin accessibility by measuring DNase I sensitivity as a continuous function of genome position using tiling DNA microarrays (DNase-array). We demonstrate this approach across 1% (|[sim]|30 Mb) of the human genome, wherein we localized 2,690 classical DNase I hypersensitive sites with high sensitivity and specificity, and also mapped larger-scale patterns of chromatin architecture. DNase I hypersensitive sites exhibit marked aggregation around transcriptional start sites (TSSs), though the majority mark nonpromoter functional elements. We also developed a computational approach for visualizing higher-order features of chromatin structure. This revealed that human chromatin organization is dominated by large (100–500 kb) 'superclusters' of DNase I hypersensitive sites, which encompass both gene-rich and gene-poor regions. DNase-array is a powerful and straightforward approach for systematic exposition of the cis-regulatory architecture of complex genomes.