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

Peter J Sabo ^{1, 6}, Michael S Kuehn ^{1, 2, 6}, Robert Thurman ^{1, 2}, Brett E Johnson ², Ericka M Johnson ², Hua Cao ², Man Yu ², Elizabeth Rosenzweig ², Jeff Goldy ¹, Andrew Haydock ¹, Molly Weaver ¹, Anthony Shafer ¹, Kristin Lee ¹, Fidencio Neri ¹, Richard Humbert ¹, Michael A Singer ³, Todd A Richmond ³, Michael O Dorschner ¹, Michael McArthur ⁴, Michael Hawrylycz ⁵, Roland D Green ³, Patrick A Navas ², William S Noble ¹, and  John A Stamatoyannopoulos ¹

¹ Department of Genome Sciences, University of Washington, 1705 NE Pacific St., Box 357730, Seattle, Washington 98195, USA.

² Division of Medical Genetics, Department of Medicine, University of Washington, 1705 NE Pacific St., Box 357730, Seattle, Washington 98195, USA.

³ Nimblegen Systems, Inc., 1 Science Court, Madison, Wisconsin 53711, USA.

⁴ Department of Microbiology, John Innes Centre, Norwich Research Park, Colney, Norwich, NR4 7UH, UK.

⁵Allen Institute for Brain Sciences, 551 N. 34th Street, Seattle, Washington 98103, USA.

⁶ These authors contributed equally to this work.
Correspondence should be addressed to John A Stamatoyannopoulos:  jstam@u.washington.edu

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% (~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.

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