Robert E Thurman, Eric Rynes, Richard Humbert, Jeff Vierstra, Matthew T Maurano, Eric Haugen, Nathan C Sheffield, Andrew B Stergachis, Hao Wang, Benjamin Vernot, Kavita Garg, Sam John, Richard Sandstrom, Daniel Bates, Lisa Boatman, Theresa K Canfield, Morgan Diegel, Douglas Dunn, Abigail K Ebersol, Tristan Frum, Erika Giste, Audra K Johnson, Ericka M Johnson, Tanya Kutyavin, Bryan Lajoie, Bum-Kyu Lee, Kristen Lee, Darin London, Dimitra Lotakis, Shane Neph, Fidencio Neri, Eric D Nguyen, Hongzhu Qu, Alex P Reynolds, Vaughn Roach, Alexias Safi, Minerva E Sanchez, Amartya Sanyal, Anthony Shafer, Jeremy M Simon, Lingyun Song, Shinny Vong, Molly Weaver, Yongqi Yan, Zhancheng Zhang, Zhuzhu Zhang, Boris Lenhard, Muneesh Tewari, Michael O Dorschner, R Scott Hansen, Patrick A Navas, George Stamatoyannopoulos, Vishwanath R Iyer, Jason D Lieb, Shamil R Sunyaev, Joshua M Akey, Peter J Sabo, Rajinder Kaul, Terrence S Furey, Job Dekker, Gregory E Crawford & John A Stamatoyannopoulos

Nature. 2012 Sep 6;489(7414):75-82. doi: 10.1038

Abstract

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ～2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ～580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase?I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.