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

PJ Sabo, MS Kuehn, R Thurman, B Johnson, EM Johnson, H Cao, M Yu, J Goldy, E Rosenzweigh, J Goldy, A Haydock, M Weaver, A Shafer, K Lee, F Neri, R Humbert, MA Singer, TA Richmond, MO Dorschner, M McArthur, M Hawrylycz, RD Green, PA Navas, WS Noble and JA Stamatoyannopoulos

Nature Methods. 3(7):511-518, 2006.


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% (approx 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.